4-Amino-5-phenyl-7-cyclobutyl-pyrrolo(2,3-d)pyrimidine derivatives

ABSTRACT

The invention relates to new 4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivatives, processes for the preparation thereof, the application thereof in a process for the treatment of the human or animal body, the use thereof-alone or in combination with one or more other pharmaceutically active compounds-for the treatment of a disease, especially a proliferative disease, such as a tumour disease, a method for the treatment of such diseases in mammals, especially in humans, and the use of such a compound-alone or in combination with one or more other pharmaceutically active compounds-for the preparation of a pharmaceutical composition (medicament) for the treatment especially of a proliferative disease, such as a tumour.

[0001] The invention relates to new4-amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine derivatives,processes for the preparation thereof, the application thereof in aprocess for the treatment of the human or animal body, the usethereof—alone or in combination with one or more other pharmaceuticallyactive compounds—for the treatment of a disease, especially aproliferative disease, such as a tumour disease, a method for thetreatment of such diseases in mammals, especially in humans, and the useof such a compound—alone or in combination with one or more otherpharmaceutically active compounds—for the preparation of apharmaceutical composition (medicament) for the treatment especially ofa proliferative disease, such as a tumour.

[0002] WO 98/41525 published on 24 Sep. 1998 discloses substituted4-amino-7H-pyrrolo[2,3-d]pyrimidines having therapeutic activity asprotein tyrosinie kinase inhibitors.

[0003] Surprisingly, it has now been found that the compounds of formulaI, described below, are potent inhibitors of the tyrosine kinaseactivity of the Insulin-like growth factor I receptor (IGF-IR) andinhibit IGF-IR-dependent cell proliferation. The pesence of thesubstituents, preferably benzyloxy substituents, at position 3 of thephenyl group of the 4amino-5-phenyl-7-cyclobutyl-pyrrolo[2,3-d]pyrimidine scaffold togetherwith the presence of the substitutent R₂ as defined herein below iscrucial for the efficacy and/or the specificity of the compounds of thepresent invention as IGF-IR tyrosine kinase inhibitors and theirpotential and/or selectivity to inhibit 1R-dependent cell proliferation.

[0004] The compounds of formula I permit, for example, an unexpected newtherapeutic approach, especially for diseases in the treatment of which,and also for the prevention of which, an inhibition of the IGF-IRtyrosine kinase and/or of the IGF-IR-dependent cell proliferation showsbeneficial effects. Such diseases include proliferative diseases, suchas tumours, like for example breast, renal, prostate, colorectal,thyroid, ovarian, pancreas, neuronal, lung, uterine and gastrointestinaltumours as well as osteosarcomas and melanomas.

[0005] The invention relates to compounds of formula I

[0006] wherein

[0007] n is from 0 to 4,

[0008] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0009] R₂ is lower alkyl substituted by hydroxy, unsubstituted, mono- ordisubstituted amino or by a heterocyclic radical; a radical R₅—(C═Y)-Z-,wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted,mono- or disubstituted amino, a heterocyclic radical, or free oretherified hydroxy, Y is oxygen, sulfur or imino, and Z is either notpresent, lower alkyl or amino-lower alkyl; or a radicalR₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro, with theproviso that R₂ is not carboxy, lower alkoxycarbonyl or lower alkylsubstituted by hydroxy if n is 0, R₁ is hydrogen, R₄ is benzyl and X is—O—,

[0010] R₃ is lower alkyl, hydroxy-, amino- or halogen-substituted loweralkyl, hydroxy, cyano, lower alkoxy, lower alkanoyl, lower alkanoyloxy,amino, mono- or di-lower alkylamino, lower alkanoylamino, carboxy, loweralkoxycarbonyl or halogen, wherein the R₃ substituents can be selectedindependently of one another if n>1,

[0011] R₄ is a radical R₇—CR₈(R₉)-, wherein R₇ is cyclobutyl,cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, thienyl or pyridyl,said R₇ substitutents being optionally substituted by one or moreradicals selected from lower alkyl and halogen, and R₈ and R₉ areindependently of each other hydrogen, lower alkyl or halogen, and

[0012] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0013] The general terms used hereinbefore and hereinafter preferablyhave within the context of this disclosure the following meanings,unless otherwise indicated:

[0014] Where compounds of formula I are mentioned, this is meant toinclude also the tautomers and N-oxides of the compounds of formula I.

[0015] Where the plural form Is used for compounds, salts, and the like,this is taken to mean also a single compound, salt, or the like.

[0016] Asymmetric carbon atoms of a compound of formula I that areoptionally present may exist in the (R), (S) or (R,S) configuration,preferably in the (R) or (S) configuration. Substituents at a doublebond or a ring may be present in cis-(=Z−) or trans (=E−) form. Thecompounds may thus be present as mixtures of isomers or as pure isomers,preferably as enantiomer-pure diastereomers.

[0017] The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either unbranched or branched withsingle or multiple branching.

[0018] Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, n-hexyl or n-heptyl.

[0019] Lower alkylene is, for example, methylene (—CH₂—), ethylene(—CH₂—CH₂—), propylene (—CH₂—CH₂—CH₂—) or tetramethylene(—CH₂—CH₂—CH₂CH₂—).

[0020] C₁-C₆alkyl or C₁-C₅alkyl are either unbranch ed or branched (withsingle or multiple branching) alkyl radicals having from 1 to 6 or from1 to 5 carbon atoms, respectively, and include methyl, ethyl, n-propyl,2-propyl, n-butyl, sec-butyl, t-butyl, and the like.

[0021] In R₂ being lower alkyl substituted by unsubstituted, mono- ordisubstituted amino or by a heterocyclic radical, lower alkyl ispreferably methyl.

[0022] Lower alkyl R₅ is preferably methyl, isopropyl or tert-butyl.

[0023] Amino-lower alkyl Z is preferably aminomethyl.

[0024] In R₆-sulfonylamino-lower alkyl, lower alkyl is preferablymethyl.

[0025] Lower alkyl R₈ is preferably methyl, ethyl or isopropyl.

[0026] Substituted lower alkyl is lower alkyl as defined above where oneor more, preferably one, substituents may be present, such as amino,N-lower alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino,N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, lower alkoxy-loweralkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, loweralkoxycarbonyl, carbamoyl, amidino, guanidino, ureido, mercapto, loweralkylthio, halogen or a heterocyclic radical.

[0027] Substituted lower alkyl R₅ is preferably lower alkyl substitutedby lower alkoxy, lower alkoxy-lower alkoxy or most preferably by aheterocyclic radical.

[0028] Halogen is primarily fluorine, chlorine, bromine, or iodine,especially fluorine, chlorine, or bromine.

[0029] Mono- or disubstituted amino is amino substituted by one or tworadicals selected independently of one another from e.g. unsubstitutedor substituted lower alkyl; phenyl or phenyl-lower alkyl wherein thephenyl radical is optionally substituted by e.g. unsubstituted orsubstituted lower alkyl, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyl, loweralkanoyloxy, cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl,amidino, guanidino, ureido, mercapto, lower alkylthio or halogen;adamantanyl; and a heterocyclic radical.

[0030] In R₂ being lower alkyl substituted by mono- or disubstitutedamino, mono- or disubstituted amino preferably represents N-loweralkylamino or N,N-di-lower alkylamino, respectively.

[0031] Mono- or disubstituted amino R₅ is preferably N-lower alkylaminoor N,N-di-lower alkylamino, respectively, wherein the lower alkyl moietyis optionally substituted by phenyl, lower alkyl-phenyl, loweralkoxy-phenyl, morpholin-yl or N,N-di-lower alkylamino.

[0032] Mono- or disubstituted amino R₆ is preferably N,N-di-loweralkylamino.

[0033] A heterocyclic radical contains especially up to 20 carbon atomsand is preferably a saturated or unsaturated monocyclic radical havingfrom 4 or 8 ring members and from 1 to 3 heteroatoms which arepreferably selected from nitrogen, oxygen and sulfur, or a bi- ortricyclic radical wherein, for example, one or two benzene radicals areannellated (fused) to the mentioned monocyclic radical. Preferred aboveall, the heterocyclic radical contains at least one nitrogen ring atomwhereby the binding of the heterocyclic radical to the radical of themolecule of formula I occurs via a nitrogen ring atom. The heterocyclicradical is optionally substituted by one or more, preferably by one ortwo, radicals such as e.g. unsubstituted or substituted lower alkyl,amino, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, loweralkoxy-lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro,carboxy, lower alkoxycarbonyl, carbamoyl, amidino, guanidino, ureido,mercapto, lower alkylthio, halogen, phenyl or pyridyl. Most preferably aheterocyclic radical is azetidinyl, pyrrolidinyl, piperidyl, azepanyl,piperazinyl, tetrahydropyranyl, morpholinyl or thiomorpholinyl, whereinsaid radicals are optionally substituted by one or more, preferably oneor two, radicals selected independently of one another from the groupconsisting of lower alkyl, hydroxy-lower alkyl, free or etherifiedhydroxy, lower alkoxycarbonyl, carbamoyl, phenyl and pyridyl and thebinding of the heterocyclic radical to the radical of the molecule offormula I occurs via a nitrogen ring atom.

[0034] In R₂ being lower alkyl substituted by a heterocyclic radical,the heterocyclic radical preferably represents azetidinyl, pyrrolidinyl,di-lower alkyl-pyrrolidinyl, aminocarbonyl-pyrrolidinyl, piperidyl,hydroxy-piperidyl, aminocarbonyl-piperidyl, azepanyl, loweralkyl-piperazinyl, lower alkoxycarbonyl-piperazinyl, phenyl-piperazinyl,pyridyl-piperazinyl, morpholinyl, di-lower alkyl-morpholin-yl orthiomorpholinyl.

[0035] In R₅ being lower alkyl substituted by a heterocyclic radical,the heterocyclic radical preferably represents piperidyl, loweralkyl-piperazinyl or morpholin-yl.

[0036] A heterocyclic radical R₅ is preferably pyrrolidinyl, piperidyl,lower alkyl-piperazinyl or morpholinyl.

[0037] Etherified hydroxy is, for example, alkoxy, especially loweralkoxy. The lower alkyl moiety of lower alkoxy is optionally substitutedby one or more, preferably one, radicals such as e.g. amino, N-loweralkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino, N,N-di-loweralkanoylamino, hydroxy, lower alkoxy, lower alkoxy-lower alkoxy, loweralkanoyl, lower alkanoyloxy, cyano, nitro, carboxy, loweralkoxycarbonyl, carbamoyl, amidino, guanidino, ureido, mercapto, loweralkylthio, halogen or a heterocyclic radical.

[0038] Etherified hydroxy R₅ is preferably lower alkoxy wherein thelower alkyl moiety is optionally substituted by lower alkoxy,N,N-di-lower alkylamino, lower alkyl-piperazinyl or morpholin-yl.

[0039] n is preferably 0.

[0040] R₁ preferably represents hydrogen, lower alkyl or halogen, mostpreferably hydrogen or lower alkyl.

[0041] R₄ is preferably benzyl.

[0042] X is preferably —O—.

[0043] Y is preferably oxygen.

[0044] Salts are especially the pharmaceutically acceptable salts ofcompounds of formula I (or an N-oxide thereof).

[0045] Such salts are formed, for example, as acid addition salts,preferably with organic or inorganic acids, from compounds of formula I(or an N-oxide thereof) with a basic nitrogen atom, especially thepharmaceutically acceptable salts.

[0046] In the presence of negatively charged radicals, such as carboxyor sulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, or ammoniumsalts with ammonia or suitable organic amines, such as tertiarymonoamines.

[0047] In the presence of a basic group and an acid group in the samemolecule, a compound of formula I (or an N-oxide thereof) may also forminternal salts.

[0048] For isolation or purification purposes it is also possible to usepharmaceutically unacceptable salts, for example picrates orperchlorates. Only the pharmaceutically acceptable salts or freecompounds (if the occasion arises, in the form of pharmaceuticalcompositions) attain therapeutic use, and these are therefore preferred.

[0049] In view of the close relationship between the novel compounds infree form and in the form of their salts, including those salts that canbe used as intermediates, for example in the purification oridentification of the novel compounds, hereinbefore and hereinafter anyreference to the free compounds is to be understood as referring also tothe corresponding salts, as appropriate and expedient.

[0050] The compounds of formula I have valuable pharmacologicalproperties, as described hereinbefore and hereinafter.

[0051] The efficacy of the compounds of the invention as inhibitors ofIGF-IGF-IR tyrosine kinase activity can be demonstrated using a cellular“Capture ELISA”. In this assay the activity of the compounds of theinvention against Insulin-like growth factor I (IGF-I) inducedautophosphorylation of the IGF-IGF-IR is determined. The assay isconducted as follows:

[0052] For the assay NIH-3T3 mouse fibroblasts transfected with humanIGF-IR cDNA (complete human IGF-IR cDNA: GenBank Acc. No. NM_(—)000875),prepared as described in Kato et al., J. Biol. Chem. 268, 2655-61, 1993,are used. The cells which overexpress human IGF-IGF-IR are cultured inDulbecco's minimal essential (DMEM) medium, containing 10% Fetal CalfSerum (FCS). For the assay 5,000 cells/well are plated on day 1 on96-well plates (Costar #3595) In normal growth medium and incubated for2 days at 37° C. in a standard CO₂ cell incubator. The density of thecells does not exceed 70-80% at day 3. On day 3 the medium is discardedand the cells are incubated for 24 h in minimal medium (DMEM, containing0.5% FCS). Compounds of formula I [starting from 10 mM dimethylsulfoxide (DMSO) stock solutions] are added to produce finalconcentrations of 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 μM to determine theIC₅₀ value. The cells are incubated for 90 min in the presence of acompound of formula I. Thereafter the cells are stimulated with 50 μlIGF-I (final concentration of IGF-I in the well =10 ng/ml; IGF-I isobtained from Sigma; Product Code: 13769) and incubated for 10 min at37° C.

[0053] The medium is discarded and the cells are washed twice with PBS/O(=Phosphate-Buffered Saline without CaCl₂) and lysed for 15 min on icewith 50 μl/well RIPA-buffer [50 mM Tris·HCl, pH=7.2, 120 mM NaCl, 1 mMEDTA, 6 mM EGTA, 1% NP −40, 20 mM NaF, 1 mM benzamidine, 15 mM sodiumpyrophosphate, 1 mM Phenyl methyl sulphonyl fluoride (PMSF) and 0.5 mMNa₃VO₄] and shaken for 10 min using a 96-well plate shaker (=cellularextracts).

[0054] Packard HTRF-96 black plates are coated with 50 μl IGF-IRmonoclonal Antibody (mAB) (Santa Cruz; Cat. No.: SC-462) in aconcentration of 5 μg/ml at 4° C. overnight. The plates are washed twicewith 0.05% (v/v) Tween-20 in Phosphate-Buffered Saline (PBS) and oncewith nanopure H₂O. Blocking is done for 2 h at room temperature (RT)with 3% Bovine Serum Albumin (BSA) in TBS-T buffer (20 mM Tris·HCl,pH=7.6, 137 mM NaCl, 0.05% Tween-20). After blocking, the plates arewashed once with nanopure H₂O.

[0055] Cellular extracts (40 μl/well) are pipetted onto the precoatedPackard plates, together with 40 μl of the anti-phosphotyrosine mousemAB PY-20 conjugated with Alkaline Phosphatase (AP) (1:1000 diluted inRIPA buffer; the antibody is obtained from Transduction Labs; Cat. No.:P11120).

[0056] After incubating the extracts and the secondary antibody for 2 hat 4° C., the extracts are discarded, the plates are washed twice with0.05% (v/v) Tween-20 in PBS and once with nanopure water.

[0057] 90 μl/well AP substrate (CDP-Star; obtained from Tropix; Cat.No.: MS100RY) are then added and the plates are incubated for 45 min atRT in the dark, followed by measuring AP activity in a Packard Top CountMicroplate Scintillation Counter. The IC₅₀ values for the compounds offormula I are calculated via linear regression analysis using theGraphPad In-stat program (GraphPad Software, USA). IC₅₀ values in therange of 5 nM to 1 μM, especially in the range of 5 nM to 300 nM arefound.

[0058] In vivo activity in the nude mouse xenotransplant model: femaleBALB/c nude mice (8-12 weeks old, Novartis Animal Farm, Sisseln,Switzerland) are kept under sterile conditions with water and feed adlibitum. Tumours are induced by subcutaneous injection of tumour cells(human epithelial cell line A-431; American Type Culture Collection(ATCC), Rockville, Md., USA, Catalogue Number ATCC CRL 1555; cell linefrom an 85-year-old woman; epidermoid carcinoma cell line) into carriermice. The resulting tumours pass through at least three consecutivetransplantations before the start of treatment. Tumour fragments (about25 mg) are implanted subcutaneously in the left flank of the animalsusing a 13-gauge trocar needle under Forene® anaesthesia (Abbott,Switzerland). Treatment with the test compound is started as soon as thetumour has reached a mean volume of 100 mm³. Tumour growth is measuredtwo to three times a week and 24 hours after the last treatment bydetermining the length of two perpendicular axes. The tumour volumes arecalculated in accordance with published methods (see Evans et al., Brit.J. Cancer 45, 466-8, 1982). The anti-tumour efficacy is determined asthe mean increase in tumour volume of the treated animals divided by themean increase in tumour volume of the untreated animals (controls) and,after multiplication by 100, is expressed as T/C %. Tumour regression(given in %) is reported as the smallest mean tumour volume in relationto the mean tumour volume at the start of treatment. The test compoundis administered daily by gavage.

[0059] As an alternative to cell line A-431, other cell lines may alsobe used in the same manner, for example:

[0060] the MCF-7 breast adenocarcinoma cell line (ATCC No. HTB 22; seealso J. Natl. Cancer Inst. (Bethesda) 51, 1409-16, 1973); and

[0061] the DU145 prostate carcinoma cell line DU 145 (ATCC No. HTB 81;see also Cancer Res. 37, 4049-58,1978).

[0062] On the basis of these studies, a compound of formula I accordingto the invention shows therapeutic efficacy especially againstproliferative diseases responsive to an inhibition of the IGF-IRtyrosine kinase.

[0063] In general, the invention relates also to the use of a compoundof formula I for the inhibition of the IGF-IR tyrosine kinase.

[0064] In addition to the inhibition of the IGF-IR tyrosine kinase, thecompounds of formula I also inhibit the tyrosine kinase activity of thereceptor tyrosine kinase Flt-3. The compounds of formula I are thereforealso useful for the treatment of proliferative diseases, especiallytumour diseases, responsive to an inhibition of the Flt-3 tyrosinekinase receptor. Such tumour diseases include e.g. leukemias andmyelodysplastic syndrome. Aberrant expression of the Flt-3 gene has beendocumented in both adult and childhood leukemias including acute myeloidleukemia (AML), AML with trilineage myelodysplasia (AML/TMDS), acutelymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS). Thecompounds of formula I are therefore suitable for the treatment of thesediseases, especially for the treatment of AML since activating mutationsof the Flt-3 receptor have been found in about 35% of patients with AML,and are associated with a poor prognosis.

[0065] The Flt-3 inhibitory activity of a compound of formula I can beshown in a tyrosine kinase inhibition assay using the cytoplasmic kinasedomain of Flt-3. The assay is performed as follows: The baculovirusdonor vector pFbacG01 (GIBCO) is used to generate a recombinantbaculovirus that expresses the amino acid region amino acids 563-993 ofthe intra-cytoplasmic kinase domain of human Flt-3. The coding sequencefor the cytoplasmic domain of Flt-3 is amplified by PCR from human c-DNAlibraries (Clontech). The amplified DNA fragments and the pFbacG01vector are made compatible for ligation by digestion with BamH1 andHindIII. Ligation of these DNA fragments results in the baculovirusdonor plasmid Flt-3(1.1). The production of the viruses, the expressionof proteins in Sf9 cells and the purification of the GST-fused proteinsare performed as follows:

[0066] Production of virus: Transfer vector (pFbacG01-Flt-3) containingthe Flt-3 kinase domain is transfected into the DH10Bac cell line(GIBCO) and the cells are plated on selective agar plates. Colonieswithout insertion of the fusion sequence into the viral genome (carriedby the bacteria) are blue. Single white colonies are picked and viralDNA (bacmid) is isolated from the bacteria by standard plasmidpurification procedures. Sf9 or Sf21 cells (American Type CultureCollection) are then transfected in 25 cm² flasks with the viral DNAusing Cellfectin reagent.

[0067] Determination of small scale protein expression in Sf9 cells:Virus containing media is collected from the transfected cell cultureand used for Infection to Increase Its titer. Virus containing mediaobtained after two rounds of infection is used for large-scale proteinexpression. For large-scale protein expression 100 cm² round tissueculture plates are seeded with 5×10⁷ cells/plate and infected with 1 mLof virus-containing media (approx. 5 MOls). After 3 days the cells arescraped off the plate and centrifuged at 500 rpm for 5 min. Cell pelletsfrom 10-20, 100 cm² plates, are resuspended in 50 mL of ice-cold lysisbuffer (25 mMTris-HCl, pH 7.5, 2 mM EDTA, 1% NP-40, 1 mM DTT, 1 mMPMSF). The cells are stirred on ice for 15 min and then centrifuged at5000 rpms for 20 min.

[0068] Purification of GST-tagged proteins: The centrifuged cell lysateis loaded onto a 2 mL glutathione-sepharose column (Pharmacia) andwashed three times with 10 mL of 25 mM Tris HCl, pH 7.5, 2 mM EDTA, 1 mMDTT, 200 mM NaCl. The GST-tagged protein is then eluted by 10applications (1 mL each) of 25 mM Tris-HCl, pH 7.5, 10 mMreduced-glutathione, 100 mM NaCl, 1 mM DTT, 10% Glycerol and stored at−70° C.

[0069] Measure of enzyme activity. Tyrosine protein kinase assays withpurified GST-Flt-3 are carried out in a final volume of 30 μL containing200-1800 ng of enzyme protein (depending on the specific activity), 20mM Tris-HCl, pH 7.6, 3 mM MnCl₂, 3 mM MgCl₂, 1 mM DTT, 10 μM Na₃VO₄, 3μg/mL poly(Glu,Tyr) 4:1, 1% DMSO, 8.0 μM ATP and 0.1 μCi [γ³³P] ATP. Theactivity is assayed in the presence or absence of inhibitors, bymeasuring the incorporation of ³³P from [γ³³P] ATP into thepoly(Glu,Tyr) substrate. The assay (30 μL) is carried out in 96-wellplates at ambient temperature for 20 min under conditions describedbelow and terminated by the addition of 20 μL of 125 mM EDTA.Subsequently, 40 μL of the reaction mixture is transferred ontoImmobilon-PVDF membrane (Millipore, Bedford, Mass., USA) previouslysoaked for 5 min with methanol, rinsed with water, then soaked for 5 minwith 0.5% H₃PO₄ and mounted on vacuum manifold with disconnected vacuumsource. After spotting all samples, vacuum is connected and each wellrinsed with 200 μL 0.5% H₃PO₄. Membranes are removed and washed 4× on ashaker with 1.0% H₃PO₄, once with ethanol. Membranes are counted afterdrying at ambient temperature, mounting in Packard Top-Count 96-wellframe, and addition of 10 μL/well of Microscint TM (Packard). IC₅₀values are calculated by linear regression analysis of the percentageinhibition of each compound in duplicate, at four concentrations(usually 0.01, 0.1, 1 and 10 μM). One unit of protein kinase activity isdefined as 1 nmole of ³³P ATP transferred from [γ³³P] ATP to thesubstrate protein per minute per mg of protein at 37° C.

[0070] In addition to the diseases mentioned above, the compounds offormula I can further be used in the treatment of obesity and are alsosuitable for the treatment of ischemic retinopathies, such as e.g.diabetic retinopathy and retinopathy of prematurity (ROP). Theeffectiveness of the compounds of formula I in these diseases can beshown by using in vitro- or in vivo-tests known in the art.

[0071] Compounds of formula I are also useful for preventing orcombating graft vessel diseases, e.g. allo- or xenotransplantvasculopathies, e.g. graft vessel atherosclerosis or chronic graftrejection, e.g. in a transplant of organ, tissue or cells, e.g. heart,lung, combined heart-lung, liver, kidney or pancreatic transplants (e.g.pancreatic islet cells), or for preventing or treating vein graftstenosis, restenosis and/or vascular occlusion following vascularinjury, e.g. caused by catherization procedures or vascular scrapingprocedures such as percutaneous transluminal angioplasty, lasertreatment or other invasive procedures which disrupt the integrity ofthe vascular intima or endothelium.

[0072] With the groups of preferred compounds of formula I mentionedhereinafter, definitions of substituents from the general definitionsmentioned hereinbefore may reasonably be used, for example, to replacemore general definitions with more specific definitions or especiallywith definitions characterized as being preferred.

[0073] Preference is given to a compound of formual I, wherein

[0074] n is from 0 to 4,

[0075] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0076] R₂ is lower alkyl substituted by hydroxy, unsubstituted, mono- ordisubstituted amino or by a heterocyclic radical; a radical R₅—(C═Y)-Z-,wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted,mono- or disubstituted amino, a heterocyclic radical, or free oretherified hydroxy, Y is oxygen, sulfur or imino, and Z is either notpresent, lower alkyl or amino-lower alkyl; or a radicalR-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro, with theproviso that R₂ is not carboxy, lower alkoxycarbonyl or lower alkylsubstituted by hydroxy if n is 0, R₁ is hydrogen, R₄ is benzyl and X is—O—,

[0077] R₃ is lower alkyl or lower alkoxy, wherein the R₃ substituentscan be selected independently of one another if n>1,

[0078] R₄ is a radical R₇—C₈(R₉)-, wherein R₇ is cyclobutyl,cyclopentyl, cyclohexyl, phenyl, furyl, pyrrolyl, thienyl, pyridyl orphenyl substituted by one or more substitutents selected from loweralkyl and halogen, and R₈ and R₉ are independently of each otherhydrogen, lower alkyl or halogen, and

[0079] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0080] Special preference Is given to a compound of formula I, wherein

[0081] n is 0,

[0082] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0083] R₂ is lower alkyl substituted by unsubstituted, mono- ordisubstituted amino or by a heterocyclic radical; a radical R₅—(C═Y)-Z-,wherein R₅ is unsubstituted or substituted lower alkyl, unsubstituted,mono- or disubstituted amino, a heterocyclic radical, or if Z is presentis also free or etherified hydroxy, Y is oxygen, sulfur or imino, and Zis either not present, lower alkyl or amino-lower alkyl; or a radicalR₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro,

[0084] R₄ is benzyl, and

[0085] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0086] Special preference is further given to a compound of formula I,wherein

[0087] n is 0,

[0088] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0089] R₂ is lower alkyl substituted by a substituted heterocyclicradical; a radical R₅—(C═Y)-Z-, wherein R₅ is unsubstituted orsubstituted lower alkyl, unsubstituted, mono- or disubstituted amino, aheterocyclic radical, or if Z is present is also free or etherifiedhydroxy, Y is oxygen, sulfur or imino, and Z is either not present,lower alkyl or amino-lower alkyl, with the proviso that Z is not presentor lower alkyl if R₅ is lower alkyl and Z is lower alkyl or amino-loweralkyl if R₅ is mono- or disubstituted amino or a heterocyclic radical;or a radical R₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstitutedor substituted lower alkyl, unsubstituted, mono- or disubstituted aminoor phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,

[0090] R₄ is benzyl, and

[0091] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0092] Preference is especially given to a compound of formula I,wherein

[0093] n is 0,

[0094] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0095] R₂ is lower alkyl substituted by amino, N-lower alkylamino,N,N-di-lower alkylamino or by an unsubstituted heterocyclic radical; ora radical R₅—(C═Y)-Z-, wherein Re is lower alkyl, mono- or disubstitutedamino or a heterocyclic radical, Y is oxygen, sulfur or imino, and Z isamino-lower alkyl if R₅ is lower alkyl and not present if R₅ is aheterocyclic radical or mono- or disubstituted amino,

[0096] R₄ is benzyl, and

[0097] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0098] Especially preferred is further a compound of formula I, wherein

[0099] n is 0,

[0100] R₁ is hydrogen, unsubstituted or substituted lower alkyl orhalogen,

[0101] R₂ is lower alkyl substituted by unsubstituted, mono- ordisubstituted amino or by a heterocyclic radical having from 4 to 8 ringmembers and from 1 to 3 heteroatoms whereby at least one heteroatom isnitrogen and the binding of the heterocyclic radical to lower alkyloccurs via a nitrogen ring atom; a radical R₅—(C═Y)-Z-, wherein R₅ islower alkyl, unsubstituted, mono- or disubstituted amino, a heterocyclicradical having from 4 to 8 ring members and from 1 to 3 heteroatomswhereby at least one heteroatom is nitrogen and the binding of theheterocyclic radical occurs via a nitrogen ring atom, lower alkylsubstituted by said heterocyclic radical or by one or more radicalsselected independently of one another from the group consisting ofamino, N-lower alkylamino, N,N-di-lower alkylamino, N-loweralkanoylamino, N,N-di-lower alkanoylamino, hydroxy, lower alkoxy, loweralkoxy-lower alkoxy, lower alkanoyl, lower alkanoyloxy, cyano, nitro,carboxy, lower alkoxycarbonyl, carbamoyl, amidino, guanidino, ureido,mercapto, lower alkylthio and halogen, or if Z is present is also freeor etherified hydroxy, Y is oxygen, sulfur or imino, and Z is either notpresent, lower alkyl or amino-lower alkyl; or a radicalRe-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro,

[0102] R₄ is benzyl, and

[0103] X is selected from —O—, —NH— and —S—, or a salt thereof.

[0104] Very especially preferred is a compound of formula I, wherein

[0105] n is 0,

[0106] R₁ is hydrogen,

[0107] R₂ is amino-lower alkyl, N-lower alkylamino-lower alkyl,N,N-di-lower alkylamino-lower alkyl, morpholinyl-lower alkyl,piperidyl-lower alkyl, pyrrolidinyl-lower alkyl, loweralkyl-piperazinyl-lower alkyl, adamantanyl-amino-lower alkyl,hydroxy-piperidyl-lower alkyl, azepanyl-lower alkyl, di-loweralkyl-pyrrolidinyl-lower alkyl, azetidinyl-lower alkyl,aminocarbonyl-piperidyl-lower alkyl, pyridyl-piperazinyl-lower alkyl,thiomorpholinyl-lower alkyl, di-lower alkyl-morpholinyl-lower alkyl,aminocarbonyl-pyrrodinyl-lower alkyl, loweralkoxycarbonyl-piperazinyl-lower alkyl or phenyl-piperazinyl-loweralkyl; a radical R₅—(C═Y)-Z-, wherein R₅ is lower alkyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-(phenyl-lower alkyl)amino,N-(lower alkyl-phenyl-lower alkyl)-amino, N-(lower alkoxy-phenyl-loweralkyl)-amino, N-(morpholinyl-lower alkyl)-amino, N,N-di-loweralkylamino-lower alkylamino, pyrrolidinyl, piperidyl, morpholinyl, loweralkyl-piperazinyl, piperidyl-lower alkyl, morpholinyl-lower alkyl, loweralkyl-piperazinyl-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,N,N-di-lower alkylamino-lower alkoxy, morpholinyl-lower alkoxy or loweralkyl-piperazinyl-lower alkoxy, Y is oxygen or imino, and Z is eithernot present or amino-lower alkyl; or a radical R-sulfonylamino-loweralkyl, wherein Ro is lower alkyl, lower alkyl-phenyl, loweralkoxy-phenyl, nitrophenyl or N,N-di-lower alkylamino,

[0108] R₄ is benzyl, and

[0109] X is —O—, or a salt thereof.

[0110] Especially preferred is further also a compound of formula I,wherein

[0111] n is 0,

[0112] R₁ is hydrogen, lower alkyl or halogen,

[0113] R₂ is a radical selected from the group consisting ofhydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, amino-lower alkyl,N-lower alkylamino-lower alkyl, (tetrahydropyranyl-amino)-lower alkyl,N,N-di-lower alkylamino-lower alkyl, N-lower alkylaminocarbonyl,N,N-di-lower alkylaminocarbonyl, guanidino-lower alkyl, loweralkyl-sulfonylamino-lower alkyl, lower alkoxy-phenyl-sulfonylamino-loweralkyl, lower alkyl-phenyl-sulfonylamino-lower alkyl,nitrophenyl-sulfonylamino-lower alkyl, N,N-di-loweralkylamino-sulfonylamino-lower alkyl, lower alkoxycarbonylamino-loweralkyl, lower alkoxy-lower alkoxycarbonylamino-lower alkyl, ureido-loweralkyl, N-lower alkylamino-carbonylamino-lower alkyl, N,N-di-loweralkylamino-carbonylamino-lower alkyl, N-(phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkyl-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkoxy-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(morpholinyl-loweralkyl)-amino-carbonylamino-lower alkyl, N,N-di-lower alkylamino-loweralkylamino-carbonylamino-lower alkyl, lower alkyl-carbonylamino-loweralkyl, piperidyl-lower alkyl-carbonylamino-lower alkyl,morpholinyl-lower alkyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-lower alkyl-carbonylamino-lower alkyl,morpholinyl-lower alkyl, piperidyl-lower alkyl, pyrrolidinyl-loweralkyl, [(hydroxy-lower alkyl)pyrrolidinyl]-lower alkyl, loweralkyl-piperazinyl-lower alkyl, adamantanyl-amino-lower alkyl,hydroxy-piperidyl-lower alkyl, azepanyl-lower alkyl, di-loweralkyl-pyrrolidinyl-lower alkyl, azetidinyl-lower alkyl,aminocarbonyl-piperidyl-lower alkyl, pyridyl-piperazinyl-lower alkyl,thiomorpholinyl-lower alkyl, di-lower alkyl-morpholinyl-lower alkyl,aminocarbonyl-pyrrodinyl-lower alkyl, loweralkoxycarbonyl-piperazinyl-lower alkyl, phenyl-piperazinyl-lower alkyl,lower alkoxy-lower alkylcarbonylamino-lower alkyl, lower alkoxy-loweralkoxy-lower alkylcarbonyl-amino-lower alkyl,pyrrolidinyl-carbonylamino-lower alkyl, piperidyl-carbonylamino-loweralkyl, morpholinyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-carbonylamino-lower alkyl, N,N-di-loweralkylamino-lower alkoxycarbonylamino-lower alkyl, morpholinyl-loweralkoxycarbonylamino-lower alkyl and lower alkyl-piperazinyl-loweralkoxycarbonylamino-lower alkyl, with the proviso that R₂ is nothydroxy-lower alkyl, carboxy or lower alkoxycarbonyl if R₁ is hydrogen,

[0114] R₄ is benzyl, and

[0115] X is —O—, or a salt thereof.

[0116] Most preferred is a compound of formula I, wherein

[0117] n is 0,

[0118] R₁ is hydrogen,

[0119] R₂ is a radical selected from the group consisting of amino-loweralkyl, N-lower alkylamino-lower alkyl, N,N-di-lower alkylamino-loweralkyl, N-lower alkylamino-carbonyl, N,N-di-lower alkylamino-carbonyl,guanidino-lower alkyl, lower alkyl-sulfonylamino-lower alkyl, loweralkoxy-phenyl-sulfonylamino-lower alkyl, loweralkyl-phenyl-sulfonylamino-lower alkyl, nitrophenyl-sulfonylamino-loweralkyl, N,N-di-lower alkylamino-sulfonylamino-lower alkyl, loweralkoxycarbonylamino-lower alkyl, lower alkoxy-loweralkoxycarbonylamino-lower alkyl, ureido-lower alkyl, N-loweralkylamino-carbonylamino-lower alkyl, N,N-di-loweralkylamino-carbonylamino-lower alkyl, N-(phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkyl-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkoxy-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(morpholinyl-loweralkyl)-amino-carbonylamino-lower alkyl, N,N-di-lower alkylamino-loweralkylamino-carbonylamino-lower alkyl, lower alkylcarbonylamino-loweralkyl, piperidyl-lower alkylcarbonylamino-lower alkyl, morpholinyl-loweralkylcarbonylamino-lower alkyl, lower alkyl-piperazinyl-loweralkylcarbonylamino-lower alkyl, morpholinyl-lower alkyl, piperidyl-loweralkyl, pyrrolidinyl-lower alkyl, lower alkyl-piperazinyl-lower alkyl,adamantanyl-amino-lower alkyl, hydroxy-piperidyl-lower alkyl,azepanyl-lower alkyl, di-lower alkyl-pyrrolidinyl-lower alkyl,azetidinyl-lower alkyl, aminocarbonyl-piperidyl-lower alkyl,pyridyl-piperazinyl-lower alkyl, thiomorpholinyl-lower alkyl, di-loweralkyl-morpholinyl-lower alkyl, aminocarbonyl-pyrrodinyl-lower alkyl,lower alkoxycarbonyl-piperazinyl-lower alkyl, phenyl-piperazinyl-loweralkyl, lower alkoxy-lower alkylcarbonylamino-lower alkyl, loweralkoxy-lower alkoxy-lower alkylcarbonylamino-lower alkyl,pyrrolidinyl-carbonylamino-lower alkyl, piperidyl-carbonylamino-loweralkyl, morpholinyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-carbonylamino-lower alkyl, N,N-di-loweralkylamino-lower alkoxycarbonylamino-lower alkyl, morpholinyl-loweralkoxycarbonylamino-lower alkyl and lower alkyl-piperazinyl-loweralkoxycarbonylamino-lower alkyl,

[0120] R₄ is benzyl, and

[0121] X is —O—, or a salt thereof.

[0122] Especially preferred is further a compound of formula I, whereinR₂ is in the 3 position of the cyclobutane ring.

[0123] Very special preference is given to a compound of formula Imentioned in the Examples below, or a salt, especially apharmaceutically acceptable salt, thereof.

[0124] Also especially preferred are all compounds of formula I, whichin the above-described “Capture ELISA” assay have an IC₅₀ value of lessthan 300 nM, most preferably those having an IC₅₀ value of less than 100nM.

[0125] The compounds of formula I or salts thereof are prepared inaccordance with processes known per se (see also WO 97/28161), thoughnot previously described for the manufacture of the compounds of theformula I, especially whereby

[0126] a) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by amino, a compound of formula II

[0127]  wherein n, R., R₃, R₄ and X have the meanings as defined for acompound of formula I, is reacted with hydrazine;

[0128] b) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is unsubstituted, mono- or disubstitutedamino, Y is oxygen and Z is not present or lower alkyl, a compound offormula III

[0129]  in which R₁₀ is a radical HO—(C═O)-Z- wherein Z is not presentor lower alkyl, and n, R₁, R₃,

[0130] R₄ and X have the meanings as defined for a compound of formulaI, is reacted with a compound of the formula R₅—H wherein Rr isunsubstituted, mono- or disubstituted amino;

[0131] c) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by mono- or disubstituted amino, a compound offormula I, in which R₂ is a radical R₅—(C═Y)Z-wherein R₅ is mono- ordisubstituted amino, Y is oxygen and Z is not present or lower alkyl, isreacted with lithium aluminium hydride;

[0132] d) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by mono- or disubstituted amino or by aheterocyclic radical containing at least one nitrogen ring atom wherebythe binding of the heterocyclic radical to lower alkyl occurs via anitrogen ring atom, a compound of formula IV

[0133]  in which R₁₁ is lower alkyl substituted by4-methylphenylsulfonyloxy and n, R₁, R₃, R₄ and X have the meanings asdefined for a compound of formula I, is reacted with a compound of theformula R₁₇—H In which R₁₇ is mono- or disubstituted amino or aheterocyclic radical containing at least one nitrogen ring atom whereinthe heterocyclic radical is attached to the hydrogen atom of R₁₇—H via anitrogen ring atom;

[0134] e) in order to prepare a compound of formula I, in which R₂ is aradical R₆-sulfonylamino-lower alkyl wherein R₆ has the meanings asdefined above under formula I, a compound of formula I, in which R₂ isamino-lower alkyl, is reacted with Re-sulfonyl halide;

[0135] f) in order to prepare a compound of formula I, In which R₂ Is aradical R₅—(C═Y)-Z- wherein R₅ is free or etherified hydroxy, Y isoxygen and Z is amino-lower alkyl, a compound of formula I, in which R₂is amino-lower alkyl, is reacted with a compound of the formulaR₅—(C═O)-Halogen wherein R₅ is free or etherified hydroxy;

[0136] g) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is unsubstituted or monosubstitutedamino, Y is oxygen or sulfur and Z is amino-lower alkyl, a compound offormula I, in which R₂ is amino-lower alkyl, is reacted with a compoundof the formula R₁₂—N═C═Y wherein Y is oxygen or sulfur, the radicalR₁₂—NH— corresponding to unsubstituted or monosubstituted amino R₅;

[0137] h) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is unsubstituted, mono- or disubstitutedamino or a heterocyclic radical containing at least one nitrogen ringatom whereby the binding of the heterocyclic radical occurs via anitrogen ring atom, Y is oxygen and Z is amino-lower alkyl, a compoundof formula I, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅ isimidazol-1-yl, Y is oxygen and Z is amino-lower alkyl, is reacted with acompound of the formula R₅—H, in which R₅ is unsubstituted, mono- ordisubstituted amino, or a heterocyclic radical which contains at leastone nitrogen ring atom;

[0138] i) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is unsubstituted or substituted loweralkyl, Y is oxygen and Z is amino-lower alkyl, a compound of formula I,in which R₂ is amino-lower alkyl, is reacted with a compound of theformula R₅—(C═O)-Halogen wherein R₅ is unsubstituted or substitutedlower alkyl;

[0139] j) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is lower alkyl substituted by aheterocyclic radical containing at least one nitrogen ring atom wherebythe binding of the heterocyclic radical to lower alkyl occurs via anitrogen ring atom, Y is oxygen and Z is amino-lower alkyl, a compoundof formula V

[0140]  in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I, is reacted with a compound of the formula R₁₈—Hin which R₁₈ is a heterocyclic radical containing at least one nitrogenring atom wherein the heterocyclic radical is attached to the hydrogenatom of R₁₈—H via a nitrogen ring atom;

[0141] k) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is lower alkylamino wherein the loweralkyl moiety is substituted by unsubstituted, mono- or disubstitutedamino or by a heterocyclic radical containing at least one nitrogen ringatom whereby the binding of the heterocyclic radical to the lower alkylmoiety occurs via a nitrogen ring atom, Y is oxygen or sulfur and Z isamino-lower alkyl, a compound of formula VI

[0142]  in which Y is oxygen or sulfur and n, R₁, R₃, R₄ and X have themeanings as defined for a compound of formula I, is reacted with acompound of the formula R₁₃—H, in which R₁₃ is unsubstituted, mono- ordisubstituted amino or a heterocyclic radical containing at least onenitrogen ring atom wherein the heterocyclic radical is attached to thehydrogen atom of R₁₃—H via a nitrogen ring atom;

[0143] l) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein

[0144] R₅ is lower alkoxy substituted by unsubstituted, mono- ordisubsUtuted amino or by a heterocyclic radical containing at least onenitrogen ring atom whereby the binding of the heterocyclic radical tothe lower alkyl moiety of lower alkoxy occurs via a nitrogen ring atom,Y is oxygen and Z is amino-lower alkyl, a compound of formula VII

[0145]  in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I, is reacted with a compound of the formula R₁₄—H,in which R₁₄ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical containing at least one nitrogen ring atom whereinthe heterocyclic radical is attached to the hydrogen atom of R₁₄—H via anitrogen ring atom;

[0146] m) in order to prepare a compound of formula I, in which R₁ ishalogen, a compound of formula I, in which R₁ is hydrogen, is reactedwith N-halosuccinimide;

[0147] n) in order to prepare a compound of formula I, in which R₁ islower alkyl, a compound of formula I, in which R₁ is halogen, is reactedwith tetra(lower alkyl) tin;

[0148] o) in order to prepare a compound of formula I, a compound offormula IX

[0149]  in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I, is reacted with a compound of formula X

[0150]  in which R₂ has the meanings as defined for a compound offormula I;

[0151] p) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by hydroxy wherein hydroxy is attached to aprimary carbon atom, a compound of formula I, in which R₂ is a radicalR₅—(C═Y)-Z- wherein R₅ is etherifed hydroxy, Y is oxygen and Z is notpresent or C₁-C₆ alkyl, is reacted with lithium aluminiumhydride;

[0152] q) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by hydroxy wherein hydroxy is attached to asecondary or tertiary carbon atom, a compound of formula XI

[0153] in which R₁₅ is a radical R₁₆—(C═O)-Q- wherein R₁₆ is hydrogen orC₁-C₅alkyl and Q is not present or C₁-C₅alkyl, is reacted with aGrignard reagent of the formula C₁-C₆alkyl-Mg-halide;

[0154] whereby functional groups which are present in the startingcompounds of processes a) to q) and are not intended to take part in thereaction, are present in protected form if necessary, and protectinggroups that are present are cleaved, whereby said starting compounds mayalso exist in the form of salts provided that a salt-forming group ispresent and a reaction in salt form is possible;

[0155] and, if so desired, a compound of formula I thus obtained isconverted into another compound of formula I, a free compound of formulaI is converted into a salt, an obtained salt of a compound of formula IIs converted into the free compound or another salt, and/or a mixture ofisomeric compounds of formula I is separated into the individualisomers.

DESCRIPTION OF THE PROCESS VARIANTS:

[0156] Regarding process a):

[0157] The reaction between a compound of formula II and hydrazine, inthe form of e.g. hydrazine monohydrate, preferably takes place in asuitable inert solvent, especially alcohols, e.g. lower alcohols, suchas ethanol and in an inert, for example an argon, atmosphere, preferablyat room temperature (RT). Hydrazine is used in excess, preferably about15 equivalents, compared to the compound of formula II.

[0158] Regarding process b):

[0159] The reaction between a compound of formula III and a compound ofthe formula R₅—H, wherein R₅ is unsubstituted, mono- or disubstitutedamino, preferably takes place in the presence ofO-(1,2-dihydro-2-oxo-1-pyridyl)-11,1,3,3-tetramethyluroniumtetrafluoroborate and diisopropylethylamine, in a suitable inertsolvent, such as for example N,N-dimethylformamide, preferably at RT.

[0160] Regarding process c):

[0161] The reaction between a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is mono- or disubstituted amino, Y isoxygen and Z is not present or lower alkyl, and lithium aluminiumhydride preferably takes place in a suitable inert solvent, such as forexample anhydrous tetrahydrofuran (THF), preferably at temperatures ofbeween 0° C. and RT, most preferably by slowly warming the reactionmixture from 0° C. to RT for about 14 hours.

[0162] Regarding process d):

[0163] The reaction between a compound of formula IV and a compound ofthe formula R₁₇—H preferably takes place at RT. If at the reactiontemperature the compound of formula R₁₇—H is in the form of a liquid andthe compound of formula IV is soluble therein, no additional solvent isneeded.

[0164] Regarding process e):

[0165] The reaction between a compound of formula I, in which R2 isamino-lower alkyl, and R₆-sulfonyl halide, in which R₆ is as definedabove under formula I, preferably takes place in the presence oftriethylamine, in a suitable inert solvent, such as for exampledichloromethane, and in an inert, for example an argon, atmosphere,preferably at about 0° C. In R₆-sulfonyl halide, halide is preferablychloride.

[0166] Regarding process f):

[0167] The reaction between a compound of formula I, in which R₂ isamino-lower alkyl, and a compound of the formula R₅—(C═O)-Halogen,wherein R₅ is free or etherifed hydroxy and Halogen is preferablychlorine, preferably takes place in the presence of triethylamine, in asuitable inert solvent, such as for example dichloromethane, preferablyat RT.

[0168] Regarding process g):

[0169] The reaction between a compound of formula I, in which R₂ isamino-lower alkyl, and a compound of the formula R₁₂—N═C═Y preferablytakes place in a suitable inert solvent, such as for exampleacetonitrile, preferably at RT.

[0170] Regarding process h):

[0171] The reaction between a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is imidazol-1-yl, Y is oxygen and Z isamino-lower alkyl, and a compound of the formula R₅—H, in which R₅ isunsubstituted, mono- or disubstituted amino, or a heterocyclic radicalwhich contains at least one nitrogen ring atom, preferably takes placein the presence of triethylamine, in a suitable inert solvent, such asfor example acetonitrile, and in an inert, for example an argon,atmosphere, preferably at RT.

[0172] Regarding process i):

[0173] The reaction between a compound of formula I, in which R₂ isamino-lower alkyl, and a compound of the formula R₅—(C═O)Halogen,wherein R₅ is unsubstituted or substituted lower alkyl and Halogen ispreferably chlorine, preferably takes place in a suitable inert solvent,such as for example N,N-dimethylformamide, preferably at RT.

[0174] Regarding process j):

[0175] The reaction between a compound of formula V and a compound ofthe formula R₁₈—H preferably takes place in a suitable inert solvent,especially alcohols, e.g. lower alcohols, such as ethanol, preferably atthe reflux temperature of the solvent employed. In a compound of formulaV, Halogen is preferably chlorine.

[0176] Regarding process k):

[0177] The reaction between a compound of formula VI and a compound ofthe formula R₁₃—H preferably takes place in a suitable inert solvent,especially alcohols, e.g. lower alcohols, such as ethanol, preferably atthe reflux temperature of the solvent employed.

[0178] In a compound of formula VI, Halogen is preferably chlorine orbromine.

[0179] Regarding process I):

[0180] The reaction between a compound of formula VII and a compound ofthe formula R₁₄—H preferably takes place in a suitable inert solvent,such as for example acetonitrile, preferably at the reflux temperatureof the solvent employed. In a compound of formula VII, Halogen ispreferably bromine.

[0181] Regarding process m):

[0182] The reaction between a compound of formula I, in which R₁ ishydrogen, and N-halosuccinimide, preferably takes place in a suitableinert solvent, such as for example N,N-dimethylformamide, and in aninert, for example an argon, atmosphere, preferably at RT in the dark.N-halosuccinimide is preferably N-bromosuccinimide.

[0183] Regarding process n):

[0184] The reaction between a compound of formula I, in which R₁ ishalogen, and tetra(lower alkyl) tin, preferably takes place in thepresence of tetrakistriphenylphosphin palladium, in a suitable inertsolvent, such as for example N,N-dimethylformamide, and in an inert, forexample an argon, atmosphere, preferably at elevated temperature such asaround 100° C.

[0185] Regarding process o):

[0186] The reaction between a compound of formula IX and a compound offormula X preferably takes place in the presence of a suitable base,such as potassium carbonate, and in the presence of 18-crown-6 ether, ina suitable inert solvent, such as for example N,N-dimethylformamide,preferably at elevated temperature such as around 80° C.

[0187] Regarding process p):

[0188] The reaction between a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ is etherified hydroxy, Y is Oxygen and Zis not present or C₁-C₆alkyl, and lithium alumini-umhydride, preferablytakes place in a suitable inert solvent, such as for example THF,preferably at around 0° C.

[0189] Regarding process q):

[0190] The reaction between a compound of formula XI and a Grignardreagent of the formula C₁-C₆alkyl-Mg-halide is carried out underconditions known in the art, for example at RT and using diethylether asthe solvent.

[0191] Additional process steps

[0192] In the additional process steps, carried out as desired,functional groups of the starting compounds which should not take partin the reaction may be present in unprotected form or may be protectedfor example by one or more protecting groups. The protecting groups arethen wholly or partly removed according to one of the known methods.

[0193] Protecting groups, and the manner in which they are introducedand removed are described, for example, in “Protective Groups in OrganicChemistry”, Plenum Press, London, New York 1973, and in “Methoden derorganischen Chemie”, Houben-Weyl, 4th edition, Vol. 15/1,Georg-Thieme-Verlag, Stuttgart 1974 and in Theodora W. Greene,“Protective Groups in Organic Synthesis”, John Wiley & Sons, New York1981. A characteristic of protecting groups is that they can be removedreadily, i.e. without the occurrence of undesired secondary reactions,for example by solvolysis, reduction, photolysis or alternatively underphysiological conditions.

[0194] The end products of formula I may however also containsubstituents that can also be used as protecting groups in startingmaterials for the preparation of other end products of formula I. Thus,within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of formula I isdesignated a “protecting group”, unless the context indicates otherwise.

[0195] A compound of formula I can be converted to a correspondingN-oxide. The reaction is carried out with a suitable oxidizing agent,preferably a peroxide, for example m-chloroperbenzoic acid, in asuitable solvent, e.g. halogenated hydrocarbon, typically chloroform ordichloromethane, or in a lower alkanecarboxylic acid, typically aceticacid, preferably at a temperature between 0° C. and the boilingtemperature of the reaction mixture, especially at about RT.

[0196] General process conditions

[0197] All process steps described here can be carried out under knownreaction conditions, preferably under those specifically mentioned, inthe absence of or usually in the presence of solvents or diluents,preferably those that are inert to the reagents used and able todissolve them, in the absence or presence of catalysts, condensingagents or neutralising agents, for example ion exchangers, typicallycation exchangers, for example in the H⁺ form, depending on the type ofreaction and/or reactants at reduced, normal, or elevated temperature,for example in the range from −100° C. to about 190° C., preferably fromabout −80° C. to about 150° C., for example at −80 to −60° C., at RT, at−20 to 40° C. or at the boiling point of the solvent used, underatmospheric pressure or in a closed vessel, if need be under pressure,and/or in an inert, for example an argon or nitrogen, atmosphere.

[0198] The invention relates also to those embodiments of the process inwhich one starts from a compound obtainable at any stage as anintermediate and carries out the missing steps, or breaks off theprocess at any stage, or forms a starting material under the reactionconditions, or uses said starting material in the form of a reactivederivative or salt, or produces a compound obtainable by means of theprocess according to the invention under those process conditions, andfurther processes the said compound in situ. In the preferredembodiment, one starts from those starting materials which lead to thecompounds described hereinabove as preferred.

[0199] In the preferred embodiment, a compound of formula I (or anN-oxide thereof) is prepared according to the processes and processsteps defined in the Examples.

[0200] The compounds of formula I (or N-oxides thereof), including theirsalts, are also obtainable in the form of hydrates, or their crystalscan include for example the solvent used for crystallisation (present assolvates).

[0201] Starting materials

[0202] New starting materials and/or intermediates, as well as processesfor the preparation thereof, are likewise the subject of this invention.In the preferred embodiment, such starting materials are used andreaction conditions so selected as to enable the preferred compounds tobe obtained.

[0203] The starting materials used in the above described processes a)to q) are known, capable of being prepared according to known processes(see also WO 97/28161), or commercially obtainable; in particular, theycan be prepared using processes as described in the Examples.

[0204] In the preparation of starting materials, existing functionalgroups which do not participate in the reaction should, if necessary, beprotected. Preferred protecting groups, their introduction and theirremoval are described above or in the examples. In place of therespective starting materials and transients, salts thereof may also beused for the reaction, provided that salt-forming groups are present andthe reaction with a salt is also possible. Where the term startingmaterials is used hereinbefore and hereinafter, the salts thereof arealways included, insofar as reasonable and possible.

[0205] A compound of formula II can be prepared for example by reactinga compound of formula VIII

[0206] wherein n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I, with phthalimide, in the presence oftriphenylphosphine and diethyl azodicarboxylate, in an inert solvent,for example dry tetrahydrofuran, and in an inert, for example an argon,atmosphere, preferably at RT.

[0207] A compound of formula VIII can be obtained according to processp) or q).

[0208] A compound of formula I, in which R₂ is a radical R₅—(C═Y)-Z-wherein R₅ is mono- or disubstituted amino, Y is oxygen and Z is notpresent or lower alkyl, can be otained according to process b).

[0209] A compound of formula IV can be prepared for example by reactinga compound of formula VIII with p-toluenesulfonyl halide, preferablyp-toluenesulfonyl chloride, in an inert solvent, for example pyridine,preferably at −20° C.

[0210] A compound of formula I, in which R₂ is amino-lower alkyl, can beobtained according to process a).

[0211] A compound of formula I, in which R₂ is a radical R₅—(C═Y)-Z-wherein R₅ is imidazol-1-yl, Y is oxygen and Z is amino-lower alkyl, canbe obtained for example by reacting a compound of formula I, in which R₂is amino-lower alkyl, with 1,1-carbonyldiimidazole, in the presence oftriethylamine, in an inert solvent, for example acetonitrile, and in aninert, for example an argon, atmosphere, preferably at RT.

[0212] A compound of formula V can be prepared for example by reacting acompound of formula I, in which R₂ is amino-lower alkyl, withhalogen-lower alkylcarbonyl halide, preferably chloro-loweralkylcarbonyl chloride, in the presence of triethylamine, in an inertsolvent, for example acetonitrile, preferably at RT.

[0213] A compound of formula VI can be obtained for example by reactinga compound of formula I, in which R₂ is amino-lower alkyl, with acompound of the formula halogen-lower alkyl-N═C═Y, wherein Y is oxygenor sulfur and halogen is preferably chlorine and bromine, in an inertsolvent, for example acetonitrile, preferably at RT.

[0214] A compound of formula VII can be prepared for example by reactinga compound of formula I, In which R₂ is amino-lower alkyl, withhalogen-lower alkyl halogen formate, preferably bromo-lower alkylchloroformate, in the presence of triethylamine, in an inert solvent,for example dichloromethane, preferably at RT.

[0215] The remaining starting materials are known, capable of beingprepared according to known processes, or commercially available; or inparticular, they can be prepared using processes as described in theExamples.

[0216] Pharmaceutical compositions, methods, uses and combinations

[0217] The present invention relates also to pharmaceutical compositionsthat comprise a compound of formula I, or a pharmaceutically acceptablesalt thereof, as active ingredient and that can be used especially inthe treatment of the diseases mentioned at the beginning.

[0218] The present invention also relates to pro-drugs of a compound offormula I that convert in vivo to the compound of formula I as such. Anyreference to a compound of formula I is therefore to be understood asreferring also to the corresponding pro-drugs of the compound of formulaI, as appropriate and expedient.

[0219] Compositions for enteral administration, such as nasal, buccal,rectal or, especially, oral administration, and for parenteraladministration, such as intravenous, intramuscular or subcutaneousadministration, to warm-blooded animals, especially humans, areespecially preferred. The compositions contain the active ingredientalone or, preferably, together with a pharmaceutically acceptablecarrier. The dosage of the active ingredient depends upon the disease tobe treated and upon the species, its age, weight, and individualcondition, the individual pharmacokinetic data, and the mode ofadministration.

[0220] The invention relates also to compounds of formula I, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition, for use in a method for the prophylactic orespecially therapeutic treatment of the human or animal body, to aprocess for the preparation thereof (especially in the form ofcompositions for the treatment of tumours) and to a method of treatingthe above-mentioned diseases, primarily tumour diseases, especiallythose mentioned above.

[0221] The invention relates also to processes and to the use ofcompounds of formula I, or a pharmaceutically acceptable salt thereof,for the preparation of pharmaceutical compositions which comprisecompounds of formula I, or a pharmaceutically acceptable salt thereof,as active component (active ingredient).

[0222] If desired, the said pharmaceutical compositions may also containfurther active components, such as other chemotherapy drugs, and/or maybe used in combination with known therapeutic processes, for example theadministration of hormonal medicines or radiation.

[0223] Preference is for a pharmaceutical composition which is suitablefor administration to a warm-blooded animal, especially humans orcommercially useful mammals suffering from a disease which responds toan inhibition of the IGF-IR tyrosine kinase or of the IGF-IR-dependentcell proliferation, especially a neoplastic disease, comprising aneffective quantity of a compound of formula I for the inhibition of theIGF-IR tyrosine kinase or of the IGF-IR-dependent cell proliferation, ora pharmaceutically acceptable salt thereof, together with at least onepharmaceutically acceptable carrier.

[0224] A pharmaceutical composition for the prophylactic or especiallytherapeutic management of neoplastic and other proliferative diseases ofa warm-blooded animal, especially a human or a commercially usefulmammal requiring such treatment, especially suffering from such adisease, comprising as active ingredient in a quantity that isprophylactically or especially therapeutically active against saiddiseases a new compound of formula I, or a pharmaceutically acceptablesalt thereof, is likewise preferred.

[0225] The pharmaceutical compositions comprise from approximately 1% toapproximately 95% active Ingredient, single-dose administration formscomprising in the preferred embodiment from approximately 20% toapproximately 90% active ingredient and forms that are not ofsingle-dose type comprising in the preferred embodiment fromapproximately 5% to approximately 20% active ingredient. Unit dose formsare, for example, coated and uncoated tablets, ampoules, vials,suppositories or capsules. Examples are capsules containing from about0.05 g to about 1.0 g of active substance.

[0226] The pharmaceutical compositions of the present invention areprepared in a manner known per se, for example by means of conventionalmixing, granulating, coating, dissolving or lyophilising processes.

[0227] The invention relates likewise to a process or a method for thetreatment of one of the pathological conditions mentioned hereinabove,especially a disease which responds to an inhibition of the IGF-IRtyrosine kinase or of the IGF-IR-dependent cell proliferation,especially a corresponding neoplastic disease. The compounds of formulaI, or a pharmaceutically acceptable salt thereof, can be administered assuch or in the form of pharmaceutical compositions, prophylactically ortherapeutically, preferably in an amount effective against the saiddiseases, to a warm-blooded animal, for example a human, requiring suchtreatment, the compounds especially being used in the form ofpharmaceutical compositions. In the case of an individual having abodyweight of about 70 kg the daily dose administered is fromapproximately 0.1 g to approximately 5 g, preferably from approximately0.5 g to approximately 2 g, of a compound of the present invention.

[0228] The present invention relates especially also to the use of acompound of formula I, or a pharmaceutically acceptable salt thereof,especially a compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, as such or in the form of apharmaceutical composition with at least one pharmaceutically acceptablecarrier, for the therapeutic and also prophylactic management of one ormore of the diseases mentioned hereinabove, preferably a disease whichresponds to an inhibition of the IGF-IR tyrosine kinase or of theIGF-IR-dependent cell proliferation, especially a neoplastic disease, inparticular if the said disease responds to an inhibition of the IGF-IRtyrosine kinase or of the IGF-IR-dependent cell proliferation.

[0229] The present invention relates especially also to the use of acompound of formula I, or a pharmaceutically acceptable salt thereof,especially a compound of formula I which is said to be preferred, or apharmaceutically acceptable salt thereof, for the preparation of apharmaceutical composition for the therapeutic and also prophylacticmanagement of one or more of the diseases mentioned hereinabove,especially a neoplastic disease, in particular if the disease respondsto an inhibition of the IGF-IR tyrosine kinase or of theIGF-IR-dependent cell proliferation.

[0230] A compound of formula I may also be used to advantage incombination with other antiproliferative agents. Such antiproliferativeagents include, but are not limited to aromatase inhibitors,antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors,microtubule active agents, alkylating agents, histone deacetylaseinhibitors, farnesyl transferase inhibitors, COX-2 inhibitors, MMPinhibitors, mTOR inhibitors, antineoplastic antimetabolites, platincompounds, compounds decreasing the protein kinase activity and furtheranti-angiogenic compounds, gonadorelin agonists, anti-androgens,bengamides, bisphosphonates and trastuzumab.

[0231] The term “aromatase inhibitors” as used herein relates tocompounds which inhibit the estrogen production, i.e. the conversion ofthe substrates androstenedione and testosterone to estrone andestradiol, respectively. The term includes, but is not limited tosteroids, especially exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, vorozole, fadrozole,anastrozole and, very especially, letrozole. Exemestane can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark AROMASIN™. Formestane can be administered, e.g., in the formas it is marketed, e.g. under the trademark LENTARON™. Fadrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark AFEMA™. Anastrozole can be administered, e.g., in the form asit is marketed, e.g. under the trademark ARIMIDEX™. Letrozole can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FEMARA™or FEMAR™. Aminoglutethimide can be administered, e.g.,in the form as it is marketed, e.g. under the trademark ORIMETEN™.

[0232] A combination of the invention comprising an antineoplastic agentwhich is an aromatase inhibitor is particularly useful for the treatmentof hormone receptor positive breast tumors.

[0233] The term “antiestrogens” as used herein relates to compoundswhich antagonize the effect of estrogens at the estrogen receptor level.The term includes, but is not limited to tamoxifen, fulvestrant,raloxifene and raloxifene hydrochloride. Tamoxifen can be administered,e.g., in the form as it is marketed, e.g. under the trademark NOLVADEX™.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA™. Fulvestrant can beformulated as disclosed in U.S. Pat. No. 4,659,516 or it can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark FASLODEX™.

[0234] The term “topoisomerase I inhibitors” as used herein includes,but is not limited to topotecan, irinotecan, 9-nitrocamptothecin and themacromolecular camptothecin conjugate PNU-166148 (compound A1 inWO99/17804). Irinotecan can be administered, e.g., in the form as it Ismarketed, e.g. under the trademark CAMPTOSAR™. Topotecan can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HYCAMTIN™.

[0235] The term “topoisomerase II inhibitors” as used herein includes,but is not limited to the antracyclines doxorubicin (including liposomalformulation, e.g. CAELYX™), epirubicin, idarubicin and nemorubicin, theanthraquinones mitoxantrone and losoxantrone, and the podophillotoxinesetoposide and teniposide. Etoposide can be administered, e.g., in theform as it is marketed, e.g. under the trademark ETOPOPHOS™. Teniposidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark VM 26-BRISTOL™. Doxorubicin can be administered, e.g., in theform as it is marketed, e.g. under the trademark ADRIBLASTIN™.Epirubicin can be administered, e.g., in the form as it is marketed,e.g. under the trademark FARMORUBICIN™. Idarubicin can be administered,e.g., in the form as it is marketed, e.g. under the trademark ZAVEDOS™.Mitoxantrone can be administered, e.g., in the form as it is marketed,e.g. under the trademark NOVANTRON™.

[0236] The term “microtubule active agents” relates to microtubulestabilizing and microtubule destabilizing agents including, but notlimited to the taxanes paclitaxel and docetaxel, the vinca alkaloids,e.g., vinblastine, especially vinblastine sulfate, vincristineespecially vincristine sulfate, and vinorelbine, discodermolide andepothilones, such as epothilone B and D. Docetaxel can be administered,e.g., in the form as it is marketed, e.g. under the trademark TAXOTERE™.Vinblastine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark VINBLASTIN R.P.™. Vincristine sulfatecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark FARMISTIN™. Discodermolide can be obtained, e.g., as disclosedin U.S. Pat. No. 5,010,099.

[0237] The term “alkylating agents” as used herein includes, but is notlimited to cyclophosphamide, ifosfamide and melphalan. Cydophosphamidecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark CYCLOSTIN™. Ifosfamide can be administered, e.g., in the formas it is marketed, e.g. under the trademark HOLOXAN™.

[0238] The term “histone deacetylase inhibitors” relates to compoundswhich inhibit the histone deacetylase and which possessantiproliferative activity.

[0239] The term “farnesyl transferase inhibitors” relates to compoundswhich inhibit the farnesyl transferase and which possessantiproliferative activity.

[0240] The term “COX-2 inhibitors” relates to compounds which inhibitthe cyclooxygenase type 2 enyzme (COX-2) and which possessantiproliferative activity such as celecoxib (Celebrex®) and rofecoxib(Vioxx®).

[0241] The term “MMP inhibitors” relates to compounds which inhibit thematrix metalloproteinase (MMP) and which possess antiproliferativeactivity.

[0242] The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCl-779and ABT578.

[0243] The term “antineoplastic antimetabolites” includes, but is notlimited to 5-fluorouracil, 5fluorouracil, tegafur, capecitabine,cladribine, cytarabine, fludarabine phosphate, fluorouridine,gemcitabine, 6-mercaptopurine, hydroxyurea, methotrexate, edatrexate andsalts of such compounds, and furthermore ZD 1694 (RALTITREXED™),LY231514 (ALIMTA™), LY264618 (LOMOTREXOL™) and OGT719.

[0244] The term “platin compounds” as used herein includes, but is notlimited to carboplatin, cisplatin and oxaliplatin. Carboplatin can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark CARBOPLAT™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN™.

[0245] The term “compounds decreasing the protein kinase activity andfurther anti-angiogenic compounds” as used herein includes, but is notlimited to compounds which decrease the activity of e.g. the VascularEndothelial Growth Factor (VEGF), the Epidermal Growth Factor (EGF) andc-Src and anti-angiogenic compounds having another mechanism of actionthan decreasing the protein kinase activity.

[0246] Compounds which decrease the activity of VEGF are especiallycompounds which inhibit the VEGF receptor, especially the tyrosinekinase activity of the VEGF receptor, and compounds binding to VEGF, andare in particular those compounds, proteins and monoclonal antibodiesgenerically and specifically disclosed in WO 98/35958 (describingcompounds of formula I), WO 00/09495, WO 00/27820, WO 00/59509, WO98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0 769 947; thoseas described by M. Prewett et al in Cancer Research 59 (1999) 5209-5218,by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp.14765-14770, December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,3209-3214, and by J. Mordenti et al in Toxicologic Pathology, vol. 27,no. 1, pp 14-21, 1999; in WO 00/37502 and WO 94/10202; Angiostatin™,described by M. S. O'Reilly et al, Cell 79, 1994, 315-328; andEndostatin™, described by M. S. O'Reilly et al, Cell 88, 1997, 277-285;compounds which decrease the activity of EGF are especially compoundswhich inhibit the EGF receptor, especially the tyrosine kinase activityof the EGF receptor, and compounds binding to EGF, and are in particularthose compounds generically and specifically disclosed in WO 97/02266(describing compounds of formula IV), EP 0 564 409, WO 99/03854, EP0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, WO 98/10767, WO97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/33980;compounds which decrease the activity of c-Src include, but are notlimited to, compounds inhibiting the c-Src protein tyrosine kinaseactivity as defined below and to SH2 interaction inhibitors such asthose disclosed in WO97/07131 and WO97/08193; compounds inhibiting thec-Src protein tyrosine kinase activity include, but are not limited to,compounds belonging to the structure classes of pyrrolopyrimidines,especially pyrrolo[2,3-d]pyrimidines, purines, pyrazopyrimidines,especially pyrazo[3,4-d]pyrimidines, pyrazopyrimidines, especiallypyrazo[3,4-d]pyrimidines and pyridopyrimidines, especiallypyrido[2,3-d]pyrimidines. Preferably, the term relates to thosecompounds disclosed in WO 96/10028, WO 97/28161, WO97/32879 andWO97/49706; anti-angiogenic compounds having another mechanism of actionthan decreasing the protein kinase activity include, but are not limitedto e.g. thalidomide (THALOMID), SU5416, and celecoxib (Celebrex).

[0247] The term “gonadorelin agonist” as used herein includes, but isnot limited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX™. Abarelixcan be formulated, eg. as disclosed in U.S. Pat. No. 5,843,901.

[0248] The term “anti-androgens” as used herein includes, but is notlimited to bicalutamide (CASODEX™), which can be formulated, e.g. asdisclosed in U.S. Pat. No. 4,636,505.

[0249] The term “bengamides” relates to bengamides and derivativesthereof having aniproliferative properties and includes, but is notlimited to the compounds generically and specifically disclosed inWO00/29382, preferably, to the compound disclosed in Example 1 ofWO00/29382.

[0250] The term “bisphosphonates” as used herein includes, but is notlimited to etridonic acid, clodronic acid, tiludronic acid, pamidronicacid, alendronic acid, ibandronic acid, risedronic acid and zoledronicacid. “Etridonic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark DIDRONEL™. “Clodronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONEFOS™. “Tiludronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark SKELID™. “Pamidronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark AREDIA™. “Alendronic acid” can be administered,e.g., in the form as it is marketed, e.g. under the trademark FOSAMAX™.“Ibandronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark BONDRANAT™. “Risedronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark ACTONEL™. “Zoledronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ZOMETA™.

[0251] “Trastuzumab” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark HERCEPTIN™.

[0252] For the treatment of AML, compounds of formula I can be used incombination with standard leukemia therapies, especially in combinationwith therapies used for the treatment of AML. In particular, compoundsof formula I can be administered in combination with e.g.farnesyl-transferase inhibitors and/or other drugs used for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin and Carboplatinum.

[0253] The structure of the active agents identified by code nos.,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

[0254] The above-mentioned compounds, which can be used in combinationwith a compound of formula I, can be prepared and administered asdescribed in the art such as in the documents cited above.

EXAMPLES

[0255] The following Examples serve to illustrate the invention withoutlimiting its scope.

[0256] Temperatures are measured in degrees Celsius. Unless otherwiseindicated, the reactions take place at RT.

[0257] Analytical HPLC conditions:

[0258] Grad 1: Linear gradient over 14 min of MeCN/0.1% TFA and H₂O/0.1%TFA from 1:4 to 1:0 and 5 min at 1:0, detection at 215 nm, flow rate 1.0ml/min. Column: Nucleosil C18-column (250×4.6 mm, 5 μm, 100 Å).

[0259] Grad 2: Linear gradient over 7 min of MeCN/0.09% TFA and H₂O/0.1%TFA from 1:49 to 1:0 and 3 min at 1:0, detection at 215 nm, flow rate2.0 ml/min. Column: Nucleosil C18-column (250×4.6 mm, 5 μm, 100 Å).

[0260] Shorty: Linear gradient over 5 min of MeCN/0.1% TFA and H₂O/0.1%TFA from 1:4 to 1:0 and 1 min at 1:0, detection at 215 nm, flow rate 1.0ml/min. Column: Nucleosil C18-column (70×4 mm, 3 μm, 100 Å).

[0261] Grad25: isocratic over 25 min of MeCN/0.1% TFA and H₂O/0.1% TFA1:1, detection at 215 nm, flow rate 1.0 m/min. Column: NucleosilC18-column (250×4.6 mm, 5 μm, 100 Å).

[0262] The short forms and abbreviations used have the followingdefinitions:

[0263] aqu. aqueous

[0264] ES-MS electron spray-mass spectroscopy

[0265] h hour(s)

[0266] Me methyl

[0267] min minute(s)

[0268] mp melting point

[0269] RT room temperature

[0270] TFA trifluoroacetic acid

[0271] THF tetrahydrofuran (distilled over Na/benzophenone)

[0272] t_(R) retention times

[0273] V volume

Example 1

[0274] To a solution of 3.84 g (7.25 mmol) ofcis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dionein 100 ml of dry ethanol are added dropwise at RT and under argon 3.75 g(3.64 ml; 74.96 mmol) of hydrazine monohydrate. After 2 h most of thestarting material is not yet dissolved, and additional 1.6 ml ofhydrazine monohydrate are added thereto (total amount: 14.8equivalents). The reaction is complete after 20 h. The colorlessprecipitate is filtered off, and washed with ethanol. The filtrate isevaporated to dryness and the crude compound is purified bychromatography on silicagel (dichloromethane:methanol:aqueousconcentrated ammonia=90:10:1) to providecis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=7.47 min (Grad 1); ES-MS: m/e, =400; ¹H-NMR(CDCl₃): 8.31/s (1H); 7.3-7.5/m (6H); 7.12/s (1H); 7.05-7.08/2 peaks(2H); 6.99/m (11H); 5.17/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.87/d(2H); 2.75-2.65/m (2H); 2.2-2.1/m (2H); 1.55/broad s (2H).

[0275] Step 1.1: To a solution of 3.5 g (8.74 mmol) ofcis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanol,which is prepared as described in Example 47(b) of WO 97/28161, in 70 mlof dry THF are added under argon 2.75 g (10.5 mmol) oftriphenylphosphine and 1.54 g (10.5 mmol) of phthalimide; 1.9 g (1.71ml; 10.5 mmol) of diethyl azodicarboxylate (96%) are added dropwisethereto. After stirring for 16 h at RT, the solution is concentrated todryness and the crude compound is purified by flash-chromatography(ethylacetate) to providecis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}isoindole-1,3-dione.Analytical HPLC: t_(R)=11.96 min (Grad 1); ES-MS: m/e_(o)=529.9.

Example 2

[0276] To a solution of 4.15 g (7.83 mmol) oftrans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dionein 100 ml of dry ethanol are added dropwise at RT and under argon 5.87 g(5.7 ml; 117.5 mmol) of hydrazine monohydrate. After 20 min all thestarting material is dissolved, and the reaction is complete after 20 hstirring at RT. The colorless precipitate is filtered off, and washedwith ethanol. The filtrate is evaporated to dryness and the crudecompound is purified by chromatography on silica gel(dichloromethane:methanol:NH₄OH_(aqu.)=90:10:1) to providetrans-7-(3-aminomethyl-cyclobutyl)-5(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=7.50 min (Grad 1); ES-MS: m/e_(o)=400; ¹H-NMR(CDCl₃): 8.30/s (1H); 7.3-7.5/m (6H); 7.20/s (1H); 7.05-7.15/2 peaks(2H); 6.99/m (1H); 5.41/m (1H); 5.14/s (2H); 5.04/broad s (2H); 2.98/d(2H); 2.54-2.69/m (2H); 2.35-2.54/m (3H); 1.73/broad s (2H).

[0277] Step 2.1: To a solution of 5 g (12.48 mmol) oftrans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol,which is prepared as described in Example 47(b) of WO 97/28161, in 100ml of dry THF are added under argon 4.91 g (18.72 mmol) oftriphenylphosphine and 2.75 g (18.7 mmol) of phthalimide; 3.36 g (3.02ml; 18.7 mmol) of diethyl azodicarboxylate (96%) are added dropwisethereto. The reaction mixture is stirred at RT for 27 h. The reactionmixture is concentrated to dryness and the crude compound is purified byflash-chromatography (ethylacetate) to obtaintrans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione.Analytical HPLC: t_(R)=12.12 min (Grad 1); ES-MS: m/e_(o)=529.9.

Example 3

[0278] To a solution of 45 mg (0.11 mmol) ofcis-3-[4-amino-5-(3benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid in 2 ml of N,N-dimethylformamide is added 36 mg (0.12 mmol) ofO-(1,2-dihydro-2-oxo-1-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate and 39 μl (0.23 mmol) of diisopropylethylamine. 40 μlof a 5.6 M solution of dimethylamine are added thereto. After stirringthe solution for 15 min at RT, working-up is effected by partitioningbetween water and ethyl acetate. The organic layer is dried overmagnesium sulfate and concentrated in vacuo to providecis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid dimethylamide. Analytical HPLC: t_(R)=6.81 min (Grad 2); ES-MS:m/e. =442.0.

[0279] Step 3.1: Thecis/trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester mixture is prepared as described in Example 47(a) ofWO 97/28161. Thecis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester is isolated from the cis/trans mixture bychromatography on silicagel (t-butyl-methyl-ether:ethylacetate=1:1).Analytical HPLC: t_(R)=10.59 min (Grad 1); ES-MS m/e_(o)=429.

[0280] Step 3.2: 0.1 g (0.23 mmol) ofcis-3-[4-amino-5(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester are dissolved in 1.8 ml of THF/1 M LiOH (1:1, v/v).After stirring at RT for 15 min, the pH of the solution is adjusted topH=6 with 2N HCl andcis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid is obtained by filtering the suspension. Analytical HPLC:t_(R)=6.61 min (Grad 2); ES-MS: m/e_(o)=415.0.

Example 4

[0281]trans-3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid dimethylamide is obtained as described in Example 3 starting withtrans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester [analytical HPLC: t_(R)=10.71 min (Grad 1); ES-MSm/e_(o)=429], which is separated from the cis/trans mixture (Example47(a) of WO 97/28161) by chromatography on silicagel(t-butyl-methyl-ether:ethylacetate=1:1). Analytical HPLC: t_(R)=6.90 min(Grad 2); ES-MS: m/e_(o)=442.0.

Example 5

[0282]cis-3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylamide is obtained as described in Example 3 using a 8.03 Msolution of methylamine in ethanol. Analytical HPLC: t_(R) 6.55 min(Grad 2); ES-MS: m/e_(o)=428.1.

Example 6

[0283]trans-3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylamide is obtained as described in Example 3 starting withtrans-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid and using a 8.03 M solution of methylamine in ethanol. AnalyticalHPLC: t_(R)=6.60 min (Grad 2); ES-MS: m/e_(o)=428.1.

Example 7

[0284] A solution of 42 mg (0.095 mmol) ofcis-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid dimethylamide in 2 ml of anhydrous THF is added dropwise at 0° C.to a 10 mg of lithium aluminium hydride suspended in 2 ml of anhydrousTHF. The reaction mixture is slowly warmed to RT overnight. Forworking-up, the reaction mixture is cooled to 0° C. and then water and a15% NaOH solution are added in succession thereto. The solution ispartitioned between water and ethyl acetate. Drying the organic layerover magnesium sulfate, concentrating in vacuo and purifying bymedium-pressure liquid chromatography yieldcis-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=5.98 min (Grad 2); ES-MS: m/e_(o)=428.1.

Example 8

[0285]trans-5-(3-Benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine is prepared as described in Example 7starting withtrans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclabutanecarboxylicacid dimethylamide. Analytical HPLC: t_(R)=6.00 min (Grad 2); ES-MS:m/e_(o)=428.1.

Example 9

[0286]cis-5-(3-Benzyloxy-phenyl)-7-(3-methylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 7 starting withcis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylamide. Analytical HP LC: t_(R)=5.96 min (Grad 2); ES-MS:m/e_(o)=414.1.

Example 10

[0287]trans-5-(3-Benzyloxy-phenyl)-7-(3-methylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 7 starting withtrans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylamide. Analytical HPLC: t_(R)=5.95 min (Grad 2); ES-MS:m/e_(o)=414.1.

Example 11

[0288] To a solution of 110 mg (0.275 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 5 ml of acetonitrile is added 72 mg (0.230 mmol) ofN,N′-bis-tert-butoxycarbonyl-1-guanylpyrazole (Advanced ChemTech Europe,Machelen, Belgium). After 16 h at RT, the mixture is diluted with 50 mlof ethylacetate and washed with water. The aqueous phases are discardedand the organic layer is dried over magnesium sulfate and evaporated todryness. The residue is dissolved in 5 ml of formic acid and thesolution is stirred for 1 h at RT. The crude mixture is purified bymedium-pressure liquid chromatography to providetrans-N-3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-guanidine.Analytical HPLC: t_(R)=6.12 min (Grad 2); ES-MS: m/e_(o)=442.0.

Example 12

[0289]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-guanidineis prepared as described in Example 11 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=6.07 min (Grad 2); ES-MS: m/e_(o)=442.0.

Example 13

[0290] To a solution of 50 mg (0.125 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 2 ml of dry dichloromethane are added at 0° C. and under argon 10 μl(0.131 mmol) of methanesulfochloride and 44 μl (0.313 mmol) oftriethylamine. After 20 h, working-up is effected by partitioningbetween water and dichloromethane. The crude product is purified bychromatography on silicagel (ethyl acetate:methanol=9:1) to yieldtrans-N-{3-[4-amino-5(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidi7-yl]-cyclobutylmethyl}-methanesulfonamide. Analytical HPLC: t_(R)=9.66min (Grad 1); ES-MS: m/e_(o)=478.0.

Example 14

[0291]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-methanesulfonamideis prepared as described in Example 13 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=6.84 min (Grad 2); ES-MS: m/e_(o)=478.0.

Example 15

[0292]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-4-methoxy-benzenesulfonamideis prepared as described in Example 13 usingp-methoxyphenylsulfochloride. Analytical HPLC: t_(R)=11.1 min (Grad 1);ES-MS: m/e_(o)=569.9.

Example 16

[0293]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}4-methyl-benzenesulfonamideis prepared as described In Example 13 using p-toluenesulfochloride.Analytical HPLC: t_(R)=11.44 min (Grad 1); ES-MS: m/e_(o)=554.

Example 17

[0294]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-4-nitro-benzenesufonamideis obtained as described in Example 13 using p-nitrophenylsulfochloride.Analytical HPLC: t_(R)=11.25 min (Grad 1); ES-MS: m/e_(o)=584.9.

Example 18

[0295] Propane-2-sulfonic acidtrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis obtained as described in Example 13 using 2-propanesulfochloride.Analytical HPLC: t_(R)=11.14 min (Grad 1); ES-MS: m/e_(o)=505.9.

Example 19

[0296] Ethanesulfonic acidtrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis obtained as described in Example 13 using ethanesulfochloride.Analytical HPLC: t_(R)=10.77 min (Grad 1); ES-MS: m/e_(o)=492.0.

Example 20

[0297] N-dimethyl-sulfamidetrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis prepared as described in Example 13 using dimethylsulfamoyl chloride(Fluka, Buchs, Switzerland). Analytical HPLC: t_(R)=7.18 min (Grad 2);ES-MS: m/e_(o)=506.9.

Example 21

[0298] N-dimethyl-sulfamidecis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis prepared as described in Example 13 usingcis7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineand dimethylsulfamoyl chloride (Fluka, Buchs, Switzerland). AnalyticalHPLC: t_(R)=7.15 min (Grad 2); ES-MS: m/e_(o)=506.9.

Example 22

[0299] To a solution of 50 mg (0.125 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 2 ml of dry dichloromethane are added at RT 12 μl (0.150 mmol) ofmethyl chloroformate (Fluka, Buchs, Switzerland) and 21 μl (0.150 mmol)of triethylamine. After stirring for 2 h at RT, working-up is effectedby partitioning between water and ethyl acetate. The organic layer isdried over magnesium sulfate and concentrated in vacuo to providetrans-{3-[4-amino-5(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid methyl ester. Analytical HPLC: t_(R)=7.08 min (Grad 2); ES-MS: m/e,=458.0.

Example 23

[0300]cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid methyl ester is prepared as described in Example 22 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4ylamine.Analytical HPLC: t_(R)=7.03 min (Grad 2); ES-MS: m/e_(o)=458.0.

Example 24

[0301]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-methoxy-ethyl ester is prepared as described in Example 22 using2-methoxyethyl chloroformate (TCI America, Portland, Oreg., U.S.A.).Analytical HPLC: t_(R)=7.04 min (Grad 2); ES-MS: m/e_(o)=502.0.

Example 25

[0302]cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-methoxy-ethyl ester is prepared as described in Example 22 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pydmidin-4-ylamineand 2-methoxyethyl chloroformate (TCI America, Portland, Oreg., U.S.A.).Analytical HPLC: t_(R)=7.02 min (Grad 2); ES-MS: m/e₀=502.0.

Example 26

[0303] To a solution of 50 mg (0.125 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 4 ml of dry acetonitrile is added at RT 16 μl (0.2 mmol) of ethylisocyanate (Fluka, Buchs, Switzerland). After stirring for 16 h at RT,working-up is effected by partitioning between water and ethyl acetate.The organic layer is dried over magnesium sulfate and evaporated todryness to providetrans-13-[4-amino-5-{3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-urea.Analytical HPLC: t_(R)=6.77 min (Grad 2); ES-MS: m/e_(o)=471.1.

Example 27

[0304]cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=6.71 min (Grad 2); ES-MS: m/e_(o)=471.0.

Example 28

[0305]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-propyl-ureais prepared as described in Example 26 using n-propyl isocyanate (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.39 min (Grad 2); ES-MS:m/e_(o) =485.0.

Example 29

[0306]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}3-propyl-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand n-propyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.33 min (Grad 2); ES-MS: m/e_(o)=484.9.

Example 30

[0307]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-isopropyl-ureais prepared as described in Example 26 using 2-propylisocyanate (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.28 min (Grad 2); ES-MS:m/e_(o)=485.0.

Example 31

[0308]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-isopropyl-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)₇H-pyrrolo[2,3-d]pyrimidin4-ylamine and2-propylisocyanate (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.37 min (Grad 2); ES-MS: m/e_(o)=484.9.

Example 32

[0309]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-butyl-ureais prepared as described in Example 26 using n-butyl isocyanate (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.53 min (Grad 2); ES-MS:m/e_(o)=499.0.

Example 33

[0310]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-butyl-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineand n-butyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.54 min (Grad 2); ES-MS: m/e_(o)=499.0.

Example 34

[0311]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-tert-butyl-ureais prepared as described in Example 26 using tert-butyl isocyanate(Fluka, Buchs, Switzerland). Analytical HPLC: t_(R)=6.60 min (Grad 2);ES-MS: m/e_(o)=499.0.

Example 35

[0312]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-tert-butyl-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand tert-butyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.61 min (Grad 2); ES-MS: m/e_(o)=499.0.

Example 36

[0313]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-benzyl-ureais prepared as described in Example 26 using benzyl isocyanate (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.88 min (Grad 2); ES-MS:m/e_(o)=532.9.

Example 37

[0314]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-methyl-benzyl)-ureais prepared as described in Example 26 using 3-methylbenzyl isocyanate(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=7.50 min (Grad 2);ES-MS: m/e_(o)=546.9.

Example 38

[0315]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-methyl-benzyl)-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand 3-methylbenzyl isocyanate (Aldrich, Buchs, Switzerland). AnalyticalHPLC: t_(R)=7.45 min (Grad 2); ES-MS: m/e, =546.9.

Example 39

[0316]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(4-methoxy-benzyl)-ureais prepared as described in Example 26 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineand 4-methoxybenzyl isocyanate (Aldrich, Buchs, Switzerland). AnalyticalHPLC: t_(R)=7.21 min (Grad 2); ES-MS: m/e₀=562.9.

Example 40

[0317] To a solution of 41 mg (0.075 mmol) oftrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-bromo-ethyl)-urea,which is prepared as described in Example 26 using 2-bromoethylisocyanate (Aldrich, Buchs, Switzerland), in 5 ml of ethanol is added 33μl (0.375 mmol) of morpholine. The mixture is refluxed for 3 h and thecrude mixture is purified by medium-pressure liquid chromatography toprovidetrans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}3-(2-morpholin-yl-ethyl)-urea.Analytical HPLC: t_(R)=6.12 min (Grad 2); ES-MS: m/e_(o)=555.9.

Example 41

[0318]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-morpholin-4-yl-ethyl)-ureais prepared as described in Example 40 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineas starting material. Analytical HPLC: t_(R)=6.04 min (Grad 2); ES-MS:m/e_(o)=555.9.

Example 42

[0319]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-dimethylamino-ethyl)-ureais prepared as described in Example 40 using dimethylamine (5.6 Msolution in ethanol; Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.08 min (Grad 2); ES-MS: m/e_(o)=514.0.

Example 43

[0320]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-dimethylamino-ethyl)-ureais prepared as described in Example 40 usingcis-7-(3-aminomethyl-cyclobutyl)₅-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineas starting material and dimethylamine (5.6 M solution in ethanol;Fluka, Buchs, Switzerland). Analytical HPLC: t_(R)=5.98 min (Grad 2);ES-MS: m/e_(o)=514.0.

Example 44

[0321]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-morpholin-4-yl-propyl)-ureais prepared as described in Example 40 using 3-chloropropyl isocyanate(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=6.12 min (Grad 2);ES-MS: m/e_(o)=569.9.

Example 45

[0322]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-morpholin4-yl-propyl)-ureais prepared as described in Example 40 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand 3-chloropropyl isocyanate. Analytical HPLC: t_(R)=5.93 min (Grad 2);ES-MS: m/e_(o)=570.0.

Example 46

[0323]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-dimethylamino-propyl)-ureais prepared as described in Example 40 using 3-chloropropyl isocyanateand dimethylamine. Analytical HPLC: t_(R)=6.09 min (Grad 2); ES-MS:m/e_(o)=528.0.

Example 47

[0324]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-dimethylamino-propyl)-ureais prepared as described in Example 40 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-]pyrimidin-4-ylamine,3-chloropropyl isocyanate and dimethylamine. Analytical HPLC: t_(R)=5.95min (Grad 2); ES-MS: m/e_(o)=528.0.

Example 48

[0325] To a solution of 50 mg (0.125 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 5 ml of methanol is added 45 mg (0.561 mmol) of potassium cyanate(Aldrich, Buchs, Switzerland). The mixture is refluxed for one week.After concentration to dryness, the residue is purified byflash-chromatography (dichloromethane:methanol=9:1) to providetrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-urea.Analytical HPLC: t_(R)=6.43 min (Grad 2); ES-MS: m/e_(o)=443.0.

Example 49

[0326]cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-ureais prepared as described in Example 48 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine.Analytical HPLC: t_(R)=6.37 min (Grad 2); ES-MS: m/e_(o)=442.9.

Example 50

[0327] To a solution of 50 mg (0.125 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 2 ml of anhydrous N,N-dimethylformamide is added 13 λl (0.138 mmol)of acetic anhydride (Fluka, Buchs, Switzerland). After stirring 1 h atRT, working-up is effected by partitioning between water and ethylacetate. The organic layer is dried over magnesium sulfate andevaporated to dryness to providetrans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamide.Analytical HPLC: t_(R)=6.65 min (Grad 2); ES-MS: m/e_(o)=442.0.

Example 51

[0328]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamideis prepared as described in Example 50 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine.Analytical HPLC: t_(R)=6.59 min (Grad 2); ES-MS: m/e_(o)=442.0.

Example 52

[0329]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-isobutyramideis prepared as described in Example 50 using isobutyril chloride (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=7.00 min (Grad 2); ES-MS:m/e_(o)=470.0.

Example 53

[0330]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isobutyramideis prepared as described in Example 50 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)₇H-pyrrolo[2,3-d]pyrimidin-4-ylamineand isobutyril chloride (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.95 min (Grad 2); ES-MS: m/e_(o)=470.0.

Example 54

[0331]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2,2-dimethyl-propionamideis prepared as described in Example 50 using pivaloyl chloride (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=7.30 min (Grad 2); ES-MS:m/e_(o)=484.0.

Example 55

[0332]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2,2-dimethyl-propionamideis prepared as described in Example 50 usingcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)₇H-pyrrolo[2,3-d]pydmidin-4-ylamineand pivaloyl chloride (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=7.25 min (Grad 2); ES-MS: m/e_(o)=484.0.

Example 56

[0333] 48 mg (0.1 mmol) oftrans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]-pyrimidin-7-yl]-cyclobutylmethyl}-2-chloro-acetamideand 25 μl (0.3 mmol) of piperidine in 5 ml of ethanol are refluxed for 2h.trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]-pyrimidin-7-yl]-cyclobutylmethyl}-2-piperidin-1-yl-acetamideis obtained after purification of the crude mixture by medium-pressureliquid chromatography. Analytical HPLC: t_(R)=6.17 min (Grad 2); ES-MS:m/e_(o)=525.0.

[0334] Step 56.1: To a suspension of 210 mg (0.53 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 10 ml of acetonitrile is added 49 μl (0.61 mmol) of chloro-acetylchloride (Fluka, Buchs, Switzerland) and 85 μl (0.61 mmol) oftriethylamine. The solution is stirred for 5 h at RT.trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-chloro-acetamideis obtained after purification of the crude mixture by medium-pressureliquid chromatography. Analytical HPLC: t_(R)=6.94 min (Grad 2); ES-MS:m/e_(o)=476.0.

Example 57

[0335]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-piperidin-1-yl-acetamide is obtained as described in Example 56starting withcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=6.14 min (Grad 2); ES-MS: m/e, =525.0.

Example 58

[0336]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-morpholin4-yl-acetamideis obtained as described in Example 56 using morpholine. AnalyticalHPLC: t_(R)=6.03 min (Grad 2); ES-MS: m/e_(o)=526.9.

Example 59

[0337]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-morpholin-4-yl-acetamideis obtained as described in Example 56 starting withcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand using morpholine. Analytical HPLC: t_(R)=5.98 min (Grad 2); ES-MS:m/e_(o)=527.0.

Example 60

[0338]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-(4-methyl-piperazin-1-yl)-acetamideis obtained as described in Example 56 using 1-methyl-piperazine.Analytical HPLC: t_(R)=5.87 min (Grad 2); ES-MS: m/e₀=539.9.

Example 61

[0339]cis-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-(4-methyl-piperazin-1-yl)-acetamideis obtained as described in Example 56 starting withcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand using 1-methyl-piperazine. Analytical HPLC: t_(R)=5.83 min (Grad 2);ES-MS: m/e_(o)=539.9.

Example 62

[0340] A solution of 50 mg (0.09 mmol) of trans-toluene-[4-sulfonic acid3-(4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester in 1 ml of morpholine (Fluka, Buchs, Switzerland) is stirred at RTfor 72 h. The solvent is evaporated to dryness and the residue ispurified by flash-chromatography(ethylacetate:methanol:NH₄OH_(aqu.)=95:5:1) to providetrans-5-(3-benzyloxy-phenyl)-7-(3-morpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=9.29 min (Grad 1); ES-MS: m/e_(o)=470.0.

[0341] Step 62.1: 200 mg (0.49 mmol) oftrans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanol,which is prepared as described In Example 47(b) of WO 97/28161, aredissolved in 2 ml of pyridine and the solution is cooled to −20° C. 153mg (0.8 mmol) of p-toluenesulfonyl chloride are added to this solutionand the reaction mixture is left overnight in the freezer at −20° C.Then, 10 ml of ice-cold water are added and the mixture is extractedwith cold dichloromethane. The aqueous phase is discarded and theorganic phase is washed with cold water/2N H₂SO₄ and water. The organiclayer is dried over magnesium sulfate and evaporated to dryness toprovide trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester, which was used in the next step without further purification.Analytical HPLC: t_(R)=13.09 min (Grad 1); ES-MS: m/e_(o)=554.9.

Example 63

[0342]trans-5-(3-Benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 using piperidine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=9.93 min (Grad 1); ES-MS:m/e_(o)=468.0.

Example 64

[0343]trans-5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 62 using pyrrolidine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=9.59 min (Grad 1); ES-MS:m/e_(o)=454.0.

Example 65

[0344]trans-5-(3-Benzyloxy-phenyl)-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 62 using 1-methyl-piperazine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=5.68 min (Grad 2); ES-MS:m/e_(o)=483.3.

Example 66

[0345] 50 mg (0.09 mmol) of trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and 34 mg (0.225 mmol) of adamantan-1-ylamine (Fluka, Buchs,Switzerland) in 1 ml N,N-dimethylformamide are stirred for 18 h at RTand for 24 h at 60° C. Additional adamantan-1-ylamine is added (34 mg)and stirring is continued for 24 h at 120° C. The solvent is evaporatedto dryness and the residue is purified by flash-chromatography(ethylacetate:methanol:NH₄OH_(aqu.)=95:5:1) to providetrans-7-[3-(adamantan-1-ylaminomethyl)cyclobutyl]-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine.Analytical HPLC: t_(R)=11.14 min (Grad 1); ES-MS: m/e_(o)=533.9.

Example 67

[0346]trans-1-{3-[4-Amino-5(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidin-4-olis prepared as described in Example 62 using 4-hydroxypiperidine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=8.52 min (Grad 1); ES-MS:m/e_(o)=484.2.

Example 68

[0347]trans-7-(3-Azepan-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 using hexamethyl-eneimine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=9.49 min (Grad 1); ES-MS:ml/e_(o)=482.3.

Example 69

[0348]trans-5-(3-Benzyloxy-phenyl)-7-[3-(2,5-dimethyl-pyrrolidin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 62 using 2,5-dimethylpyrrolidine(cis/trans) (Brunswig Chemie, Basel, Switzerland). Analytical HPLC:t_(R)=9.38 min (Grad 1); ES-MS: m/e_(o)=482.2.

Example 70

[0349]trans-7-(3-Azetidin-1-ylmethyl-cyclobutyl)₅-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 using trimethyleneimine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=8.89 min (Grad 1); ES-MS:m/e_(o)=440.2.

Example 71

[0350]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidine-3-carboxylicacid amide is prepared as described in Example 62 using R,S-nipecotamide(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=8.52 min (Grad 1);ES-MS: m/e_(o)=511.0.

Example 72

[0351]trans-5-(3-Benzyloxy-phenyl)-7-[3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 62 using 1-(2-pyridyl)-piperazine(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=8.15 min (Grad 1);ES-MS: m/e. =546.2.

Example 73

[0352]trans-5-(3-Benzyloxy-phenyl)-7-(3-thiomorpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 using thiomorpholine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=9.26 min (Grad 1); ES-MS:m/e_(o)=486.2.

Example 74

[0353]trans-5-(3-Benzyloxy-phenyl)-7-[3-(2,6-dimethyl-morpholin4-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 usingcis/trans-2,6-dimethylmorpholine (Fluka, Buchs, Switzerland). AnalyticalHPLC: t_(R)=9.39 min (Grad 1); ES-MS: m/e_(o)=498.2.

Example 75

[0354]trans-(S)1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-pyrrolidine-2-carboxylicacid amide is prepared as described in Example 62 using L-prolinamide(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=8.56 min (Grad 1);ES-MS: m/e_(o)=497.2.

Example 76

[0355]cis-7-(3-Azepan-1-ylmethyl-cyclobutyl-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 62 usingcis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanol,which is prepared as described in Example 47(b) of WO 97/28161, asstarting material and hexamethyleneimine (Fluka, Buchs, Switzerland).Analytical HPLC: t_(R)=9.51 min (Grad 1); ES-MS: m/e_(o)=482.2.

Example 77

[0356]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidin-4-olis prepared as described in Example 76 using 4-hydroxypiperidine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=8.36 min (Grad 1); ES-MS:m/e_(o)=484.2.

Example 78

[0357]cis-4-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}piperazine-1-carboxylicacid ethyl ester is prepared as described in Example 76 using1-ethoxycarbonylpiperazine (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=9.23 min (Grad 1); ES-MS: m/e_(o)=541.2.

Example 79

[0358]cis-5-(3-Benzyloxy-phenyl)-7-[3-(4-phenyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 76 using 1-phenylpiperazine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=10.24 min (Grad 1); ES-MS:m/e_(o)=545.1.

Example 80

[0359]cis-5-(3-Benzyloxy-phenyl)-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 76 using 1-methylpiperazine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=7.87 min (Grad 1); ES-MS:m/e_(o)=483.2.

Example 81

[0360]cis-5-(3-Benzyloxy-phenyl)-7-(3-thiomorpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 76 using thiomorpholine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=9.08 min (Grad 1); ES-MS:m/e_(o)=486.1.

Example 82

[0361]cis-5-(3-Benzyloxy-phenyl)-7-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 76 usingcis/trans-2,6-dimethylmorpholine (Fluka, Buchs, Switzerland). AnalyticalHPLC: t_(R)=9.27 min (Grad 1); ES-MS: m/e_(o)=498.2.

Example 83

[0362]cis-(R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-pyrrolidine-2-carboxylicacid amide is prepared as described in Example 76 using L-prolinamide(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=8.53 min (Grad 1);ES-MS: m/e_(o)=497.1.

Example 84

[0363]cis-1-(3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidine-3-carboxylicacid amide is prepared as described in Example 76 using L,D-nipecotamide(Aldrich, Buchs, Switzerland). Analytical HPLC: t_(R)=8.46 min (Grad 1);ES-MS: m/e_(o)=511.2.

Example 85

[0364]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-ethoxy-acetamideis prepared starting fromtrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamineand ethoxy-acetic acid (Fluka, Buchs, Switzerland) according to aprocedure known in the art (M. Bodanszky in Principles of PeptideSynthesis, Akad.-Verlag, 1984). Analytical HPLC: t_(R)=7.07 min (Grad2); ES-MS: m/e_(o)=486.2.

Example 86

[0365]trans-N-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-2-(2-methoxy-ethoxy)acetamideis prepared starting fromtrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand 2-(2-methoxyethoxy)-acetic acid (Fluka, Buchs, Switzerland)according to a procedure known in the art (M. Bodanszky in Principles ofPeptide Synthesis, Akad.-Verlag, 1984). Analytical HPLC: t_(R)=6.91 min(Grad 2); ES-MS: m/e_(o)=516.2.

Example 87

[0366]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}3-methyl-ureais prepared as described in Example 26 starting with methyl isocyanate(ChemService Inc., West Chester, Pa., U.S.A.). Analytical HPLC:t_(R)=6.55 min (Grad 2); ES-MS: m/e_(o)=457.0.

Example 88

[0367]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-3-methyl-ureais prepared as described in Example 26 starting withcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineand methyl isocyanate (ChemService Inc., West Chester, Pa., U.S.A.).Analytical HPLC: t_(R)=6.49 min (Grad 2); ES-MS: m/e_(o)=456.9.

Example 89

[0368] To a suspension of 0.2 g (0.5 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylaminein 5 ml of acetonitrile are added under argon 108 mg (0.65 mmol) of1,1-carbonyldiimidazole (Fluka, Buchs, Switzerland) and 628 μl (4.5mmol) of triethylamine. The reaction mixture is stirred for 15 min at RTand 414 μl (5.0 mmol) of pyrrolidine (Fluka, Buchs, Switzerland) areadded thereto. After stirring for 2.5 h at RT, the reaction mixture isconcentrated and the crude compound is purified by reversed-phase mediumpressure chromatography to provide trans-pyrrolidine-1-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide.Analytical HPLC: t_(R)=7.02 min (Grad 2); ES-MS: m/e_(o)=497.2.

Example 90

[0369] trans-Piperidine-1-carboxylic acid{-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis prepared as described in Example 89 using piperidine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=7.30 min (Grad 2); ES-MS:m/e_(o)=511.2.

Example 91

[0370] trans-Morpholine-4-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cydobutylmethyl)-amideis prepared as described in Example 89 using morpholine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=6.72 min (Grad 2); ES-MS:m/e_(o)=513.2.

Example 92

[0371]trans-3-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-1,1-dimethyl-ureais prepared as described in Example 89 using dimethylamine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.82 min (Grad 2); ES-MS:m/e_(o)=471.3.

Example 93

[0372] trans-4-Methyl-piperazine-1-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amideis prepared as described in Example 89 using 1-methyl-piperazine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=6.01 min (Grad 2); ES-MS:m/e_(o)=526.2.

Example 94

[0373]trans-(3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-1,1-diethyl-ureais prepared as described in Example 89 using diethylamine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=7.22 min (Grad 2); ES-MS:m/e_(o)=499.2.

Example 95

[0374] To a solution of 0.2 g (0.5 mmol) oftrans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylaminein 5 ml of dichloromethane are added 55.4 μl (0.5 mmol) of 2-bromoethylchloroformate (Fluka, Buchs, Switzerland) and 70 μl (0.5 mmol) oftriethylamine. After stirring for 2 h at RT, the solution isconcentrated to dryness. The crude compound is dissolved in 5 ml ofacetonitrile and 260 μl (2.5 mmol) of diethylamine (Fluka, Buchs,Switzerland) are added thereto. The reaction mixture is refluxed for 16h and, after concentration, the crude compound is purified bymedium-pressure liquid chromatography to providetrans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-diethylamino-ethyl ester. Analytical HPLC: t_(R)=6.27 min (Grad2); ES-MS: m/e_(o)=543.3.

Example 96

[0375]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-carbamicacid 2-morpholin-4-yl-ethyl ester is prepared as described in Example 95using morpholine (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.18 min (Grad 2); ES-MS: m/e_(o)=557.2.

Example 97

[0376]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-carbamicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester is prepared as described inExample 95 using 1-methyl-piperazine (Fluka, Buchs, Switzerland).Analytical HPLC: t_(R)=5.88 min (Grad 2); ES-MS: m/e_(o)=570.2.

Example 98

[0377]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cydobutylmethyl}-carbamicacid 2-dimethylamino-ethyl ester is prepared as described in Example 95using dimethylamine (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=6.14 min (Grad 2); ES-MS: m/e. =515.2.

Example 99

[0378]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-carbamicacid ethyl ester is prepared as described in Example 22 using ethylchloroformate (Fluka, Buchs, Switzerland). Analytical HPLC: t_(R)=7.32min (Grad 2); ES-MS: m/e_(o)=472.2.

Example 100

[0379]trans-4-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperazine-1-carboxylicacid ethyl ester is prepared as described in Example 62 using1-ethoxycarbonylpiperazine (Fluka, Buchs, Switzerland). Analytical HPLC:t_(R)=9.25 min (Grad 1); ES-MS: m/e_(o)=541.2.

Example 101

[0380]cis-5-(3-Benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7-H-pyrrolo[2,3-d]pyrimidin4-ylamineis prepared as described in Example 76 using pyrrolidine (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=9.01 min (Grad 1); ES-MS: m/e.=454.2.

Example 102

[0381]cis-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamineis prepared as described in Example 76 using trimethyleneimine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=8.80 min (Grad 1); ES-MS:m/e_(o)=440.2.

Example 103

[0382]trans-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylester

[0383] To 11 g (25.67 mmol)trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester (see Example 4) in 275 ml dry N,N-dimethylformamide,5.18 g (28.24 mmol) N-bromosuccinimide are added in small portions. Thesolution is stirred at RT in the dark and under Argon for 17 h.Thereafter the solvent is evaporated, and the residue purified bychromatography on silicagel (solvent: hexane-ethyl acetate 3:1). Furtherpurification is done by crystallization from acetonitrile. AnalyticalHPLC: t_(R)=3.61 min (shorty); ES-MS: m/e_(o)=506.9 and 508.9; mp:124-125° C.; NMR (DMSO-d6): 8.18/s(1H), 7.25-7.5/several m's(6H),7.09/“d”(1H); 7.04/s(1H); 6.98/“d”(1H); 5.38/m (1H); 5.13/s (2H); 3.69/s(3H); 3.50/m (2H); 3.29/m (1H); 2.62/m (2H).

Example 104

[0384]trans-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester

[0385] In a sealed tube, 4.68 g (9.02 mmol)trans-3-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylester of Example 103, 2.08 g (1.8 mmol)tetrakistriphenylphosphin palladium and 5.3 ml (38.05 mmol) tintetramethyl (Fluka, Buchs, Switzerland) are heated under Argon in 20 mldry N,N-dimethylformamide for 30 h at 100-105° C. bath temperature. Thereaction mixture is filtered on hyflo (Hyflo Super Cel®; Fluka, Buchs,Switzerland), and the residue washed thouroughly withN,N-dimethylformamide. The dark filtrate is evaporated at 60° C. todryness, the residual mass dissolved in hot ethyl acetate andchromatographed on silicagel (hexane-ethyl acetate 25:75). The titlecompound is obtained as yellow crystals. Analytical HPLC: t_(R)=3.54 min(shorty); ES-MS: m/e_(o)=443; NMR (DMSO-d6): 8.08/s(1H),7.25-7.5/several m's(6H), 6.99/“d”(1H); 6.90/s(1H); 6.85/“d”(1H); 5.09/s(2H); 5.06/m (1H); 3.64/s (3H); 3.2-3.5/2×m (3H); 2.59/m (2H); 2.18/s(3H).

Example 105

[0386]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol2.94 g (6.64 mmol)trans-3-[4-amino-5-(3-benzyloxy-phenyl)₆-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester of Example 104 in 35 ml dry THF are added during 45min to an ice-cold solution of 0.281 g (7.17 mmol) lithiumaluminiumhydride in 30 ml dry THF. The reaction mixture is stirred at 0°C. for additional 20 h. Water is added slowly to the mixture (0.914 mlin 20 min; T≦∝° C.), followed by 0.11 ml 4N NaOH. The precipitate isfiltered off, the residue on the filter washed with ethyl acetate andwater. The filtrate is extracted with ethyl acetate. After drying theorganic phase with sodium sulfate, the solvent is evaporated and theresidue purified by chromatography (solvent: ethyl acetate-MeOH 95:5).The title compound is obtained as a foam. Analytical HPLC: t_(R)=3.06min (shorty); ES-MS: m/e_(o)=415; NMR (DMSO-d6): 8.10/s(1H),7.25-7.5/several m's(6H), 7.25/“d”(1H); 6.95/s(1H); 6.90/1“d”(1H);5.5-6.0/b (NH2); 5.13/s (2H); 5.04/m (1H); 4.69/t (OH); 3.57/t (2H);3.15-3.25/m (2H); 2.4-2.5/m (1H); 2.23/s (3H); 2.15-2.25/m (2H).

Example 106

[0387] trans-Toluene-4-sulfonic add3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester

[0388] 2.57 g (6.17 mmol)trans-3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanolof Example 105 are dissolved in 50 ml dry pyridine. The solution iscooled to ca. −25° C. and 2.04 g (10.5 mmol) p-toluenesulfonyl chlorideare added in 4 portions. After stirring 3 h at −20° C. and 24 h at 0-5°C., additional p-toluenesulfonyl chloride (0.36 g; 1.85 mmol) is addedand stirring is continued for additional 19 h. The reaction mixture ispoured into ice-water and extracted with dichloromethane. The organicphase is washed with water and brine. After evaporating the organicsolvent, the residue is purified by filtration on silicagel (ethylacetate-hexane 3:1). The compound is dried at RT and under high-vacuumfor 18 h. Analytical HPLC: t_(R)=4.12 min (shorty); ES-MS:m/e_(o)=569.2; NMR (DMSO-d6): 8.09/s(1H), 7.84/d (2H); 7.25-7.6/severalm's(8H), 7.06/“d”(1H); 6.93/s(1H); 6.88/“d”(1H); 5.5-6.0/b (NH2); 5.13/s(2H); 5.00/m (1H); 4.26/d (2H); 3.15-3.35/m (2H); 2.69/m (1H); 2.42/s(3H); 2.17/s (3H); 2.42/s (3H); 2.05-2.20/m (2H).

Example 107

[0389]trans-5-(3-Benzyloxy-phenyl)-6-methyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0390] 0.335 g (0.589 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester of Example 106 in 3.6 ml pyrrolidine are stirred at RT for 3.5 h(Thin Layer Chromatography and HPLC control). The excess reagent isevaporated on a rotavap and the residue purified by chromatography(solvent: ethyl acetate-MeOH-aqu. NH₃ (33%) 95:5:1). The compound iscrystallized from diethylether. Analytical HPLC: t_(R)=9.09 min (Grad1); mp: 136-140° C.; ES-MS: m/e_(o)=468.3; NMR (DMSO-d6; not all signalsreported): 8.10/s(1H), 7.25-7.5/several m's(6H), 7.02/“d”(1H);6.94/s(1H); 6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.06/m (1H);2.22/s (3H).

Example 108

[0391]trans-5-(3-Benzyloxy-phenyl)-6-methyl-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0392] The title compound is obtained in analogy to Example 107 from0.35 g (0.615 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and 3.5 ml (31.2 mmol) 1-methyl piperazine (RT; reaction time 24h). Analytical HPLC: t_(R)=2.32 min (shorty); ES-MS: m/e_(o)=497.3; NMR(DMSO-d6; not all signals reported): 8.09/s(1H), 7.25-7.5/severalm's(6H), 7.01/“d”(1H); 6.94/s(1H); 6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s(2H); 5.07/m (1H); 2.22/s (3H); 2.13/s (3H).

Example 109

[0393]trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidin-4-ol

[0394] The title compound is obtained in analogy to Example 107 from0.35 g (0.615 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and a total of 0.44 g (4.3 mmol) 4-hydroxy piperidine in 3.5 ml ofdry N,N-dimethyl acetamide (RT; 144 h; after 46 h 64 mg of reagent areadded to complete the reaction). Analytical HPLC: t_(R)=2.54 min(shorty); ES-MS: m/e_(o)=498.3; NMR (DMSO-d6; not all signals reported):8.09/s(1H), 7.25-7.5/several m's(6H), 7.01/“d”(1H); 6.94/s(1H);6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.06/m (1H); 4.51/d (OH);2.22/s (3H).

Example 110

[0395]trans-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-6-methyl-7-H-pyrrolo[2,3-d]pyrimidin4-ylamine

[0396] The title compound is obtained in analogy to Example 107 from0.35 g (0.65 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin7-yl]-cyclobutylmethylester and 0.215 ml (3.08 mmol) trimethylenimin (Fluka, Buchs,Switzerland) in 3.5 ml N,N-dimethylacetamide (RT; reaction time 120 h).Analytical HPLC: t_(R)=8.97 min (Grad 1); ES-MS: m/e_(o)=454.3; NMR(DMSO-d6): 8.09/s(1H), 7.25-7.5/several m's(6H), 7.01/“d”(1H);6.93/s(1H); 6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.02/m (1H); ca.3.3/m (1H); 3.2/m (2H); 3.10/t (2H); 2.54/d (2H); 2.30/m (1H); 2.21/s(3H); 2.11/m (2H); 1.94/m (2H).

Example 111

[0397]trans-5-(3-Benzyloxy-phenyl)-6-methyl-7-{3-[(tetrahydro-pyran-4-ylamino)-methyl]-cyclobutyl}-7H-pyrrolo[2,3-d]pyrimidin4-ylamine

[0398] The title compound is obtained in analogy to Example 107 from0.35 g (0.62 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and 0.446 mg (4.42 mmol) tetrahydropyran-4-ylamin (obtained fromtetrahydropyran-4-one oxime by hydrogenation) in 3.5 mlN,N-dimethylacetamide (RT; reaction time 310 h). Analytical HPLC:t_(R)=8.99 min (Grad 1); ES-MS: m/e_(o)=498.3; NMR (DMSO-d6; not allsignals reported): 8.09/s(1H), 7.25-7.5/several m's(6H), 7.02/“d”(1H);6.94/s(1H); 6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.06/m (1H);3.82/m (2H); 2.75/d (2H); 2.23/s (3H).

Example 112

[0399]trans-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-pyrrolidin-2-yl)-methanol

[0400] The title compound is obtained in analogy to Example 107 from0.35 g (0.62 mmol) trans-toluene-4-sulfonic acid3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethylester and 0.307 ml (3.08 mmol) D-prolinol (Fluka, Buchs, Switzerland) in3.5 ml N,N-dimethylacetamide (RT; reaction time 114 h). Analytical HPLC:t_(R)=8.95 min (Grad 1); ES-MS: m/e_(o)=498.3; NMR (DMSO-d6; not allsignals reported): 8.10/s(1H), 7.25-7.5/several m's(6H), 7.02/“d”(1H);6.94/s(1H); 6.92/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 5.06/m (1H);4.37/bs (OH); 2.23/s (3H).

Example 113

[0401]cis-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester

[0402] The title compound is prepared in analogy to Example 103 startingfrom 12.9 g (30.11 mmol)cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutanecarboxylicacid methyl ester (see Step 3.1 above) and 6.07 g (33.12 mmol)N-bromosuccinimide in 250 ml dry N,N-dimethylformamide. After work-up,the raw material is purified by chromatography on silicagel (solvent:hexane-ethyl acetate 1:1). Analytical HPLC: t_(R)=11.85 min (Grad 1);ES-MS: m/e_(o)=506.9 and 509.9; NMR (DMSO-d6): 8.14/s(1H),7.3-7.5/several m's(6H), 7.09/“d”(1H); 7.05/s(1H); 6.98/“d”(1H);5.5-6.5/b (NH2); 5.13/s (2H); 5.11/m (1H); 3.66/s (3H); 3.35-3.5/m (2H);3.08/m (1H); 2.58-2.7/m (2H).

Example 114

[0403]cis-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester

[0404] The title compound is prepared in analogy to Example 104 startingfrom 6.6 g (12.6 mmol)cis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutane-carboxylicacid methyl ester of Example 113, 0.364 g (0.315 mmol) tetrakistriphenylpalladium, and 4.39 ml (31.52 mmol) tin tetramethyl (Fluka, Buchs,Switzerland) in 20 ml dry N,N-dimethylformamide (T=100-110° C., sealedtube; reaction time=25 h). Analytical HPLC: t_(R)=11.67 min (Grad 1);ES-MS: m/e_(o)=443.2; NMR (DMSO-d6; not all signals reported):8.07/s(1H), 7.25-7.5/several m's(6H), 7.03/“d”(1H); 6.95/s(1H);6.90/“d”(1H); 5.5-6.0/b (NH2); 5.14/s (2H); 4.90/m (1H); 3.65/s (3H);2.25/s (3H).

Example 115

[0405]cis-{3-[4-Amino-5-3-benyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol

[0406] The title compound is obtained in analogy to Example 105 startingfrom 2.06 gcis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-y]-cyclobutanecarboxylicacid methyl ester of Example 114 and 0.216 mmol lithium aluminiumhydridein 20 ml dry THF (T=0-5° C.; reaction time 49 h). The product ispurified by flash chromatography (solvent: ethyl acetate). AnalyticalHPLC: t_(R)=3.13 min (shorty); ES-MS: m/e_(o)=415.4; NMR (DMSO-d6):8.07/s(1H), 7.25-7.5/several m's(6H), 7.02/“d”(1H); 6.94/s(1H);6.89/“d”(1H); 5.5-6.0/b (NH2); 5.13/s (2H); 4.84/m (1H); 4.62/t (OH);3.53/t (2H); 2.8-2.9/m (2H); 2.35-2.45/m (2H); 2.24/s (3H); 2.2/m (1H).

Example 116

[0407]cis-5-(3-Benzyloxy-phenyl)-6-methyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7-H-pyrrolo[2,3-d]pyrimidin4-ylamine

[0408] To a solution of 0.2 g (0.48 mmol)cis-{3-[4-amino-5-(3-benzyloxy-phenyl-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 115 in 2 ml dry pyridine cooled to ca. −25° C. 0.159 g (0.96mmol) p-toluenesulfonyl chloride are added in 1 h in three portions.Stirring continued for 1 h at −20° C. and overnight at 0° C. To thisreaction mixture is added in 1 h under Argon 2 ml of pyrrolidine (T=0-5°C.) and stirring is continued for additional 3 h. The reaction mixtureis partitioned between ethyl acetate and water. After drying with sodiumsulfate the solvent is evaporated and the residue purified by flashchromatography (solvent: ethyl acetate-MeOH-NH₃ aqu. (33%) 95:5:1).Analytical HPLC: t_(R)=9.28 min (Grad 1); ES-MS: m/e_(o)=468.2; NMR(DMSO-d6): 8.08/s(1H), 7.25-7.5/several m's(6H), 7.02/“d”(1H);6.94/s(1H); 6.89/“d”(1H); 5.4-5.9/b (NH2); 5.13/s (2H); 4.77/m (1H);2.8-2.9/m (2H); 2.60/d (2H); 2.35-ca. 2.5/m (6H); 2.23/s (3H); ca.2.15-2.25/m (1H); 1.6-1.7/m (4H).

Example 117

[0409]cis-5-(3-Benzyloxy-phenyl)-6-methyl-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0410] The title compound is prepared in a one pot reaction in analogyto Example 116 starting from 0.35 g (0.84 mmol)cis-{3-[4-amino-5-(3-benyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanoland 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml drypyridine, followed by 3.5 ml (31.2 mmol) 1-methyl piperazine. AnalyticalHPLC: t_(R)=8.14 min (Grad 1); ES-MS: m/e_(o)=497.3; NMR (DMSO-d6; notall data reported): 8.08/s(1H), 7.25-7.45/several m's(6H), 7.02/“d”(1H);6.94/s(1H); 6.89/“d”(1H); 5.4-6.0/b (NH2); 5.13/s (2H); 4.77/m (1H);2.22/s (3H); 2.12/s (3H).

Example 118

[0411]cis-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0412] The title compound is prepared in analogy to Example 116 startingfrom 0.35 g (0.84 mmol)cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanoland 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml drypyridine, followed by 0.442 ml (6.33 mmol) trimethylenimine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=9.22 min (Grad 1); ES-MS:m/e_(o)=454.3; NMR (DMSO-d6): 8.08/s(1H), 7.25-7.5/several m's(6H),7.02/“d”(1H); 6.93/s(1H); 6.89/“d”(1H); 5.4-6.0/b (NH2); 5.13/s (2H);4.76/m (1H); 3.11/“t”(4H); 2.75-2.90/m (2H); 2.54/d (2H); 2.35-2.45/m(2H); 2.22/s (3H); 2.03/m (1H); 1.9-2.0/m (2H).

Example 119

[0413]cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidin4-ol

[0414] The title compound is prepared in analogy to Example 116 startingfrom 0.35 g (0.84 mmol)cis-{3-[4-amino-5-(3-benyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanoland 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml drypyridine, followed by 0.87 g (8.44 mmol) 4-hydroxypiperidine (Fluka,Buchs, Switzerland). Analytical HPLC: t_(R)=8.76 min (Grad 1); ES-MS:m/e_(o)=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s(1H),7.25-7.5/several m's(6H), 7.01/“d”(1H); 6.94/s(1H); 6.89/“d”(1H); 5.13/s(2H); 4.76/m (1H); 4.51/d (OH); 2.22/s (3H).

Example 120

[0415]cis-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-pyrrolidin-2-yl)-methanol

[0416] The title compound is prepared in analogy to Example 116 startingfrom 0.35 g (0.84 mmol)cis-{3-[4-amino-5-(3-benyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanoland 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml drypyridine, followed by 0.631 ml (6.33 mmol) D-prolinol (Fluka, Buchs,Switzerland). Analytical HPLC: t_(R)=9.08 min (Grad 1); ES-MS:m/e_(o)=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s(1H),7.25-7.5/several m's(6H), 7.02/“d”(1H); 6.94/s(1H); 6.89/“d”(1H);5.4-6.0/b (NH2); 5.13/s (2H); 4.78/m (1H); 4.34/b (OH); 2.22/s (3H).

Example 121

[0417]5-(3-Benzyloxy-phenyl)-6-bromo-7H-pyrrolo[2,3-d]pyrimidin4-ylamineTo a solution of 20 g (63.2 mmol)5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (see WO97/28161) in 1 l dry N,N-dimethylformamide, 12.4 g (69.5 mmol)N-bromosuccinimide are added at ca. 10° C. Stirring was continued at ca.10° C. for 30 min and overnight at RT. The precipitate formed isfiltered off and washed thoroughly with N,N-dimethylformamide andhexane. After drying for 24 h at 30-35 CC under vacuum, the titlecompound is used in the next step without further purification.Additional material can be obtained from the mother liquor throughchromatography on silicagel. Analytical HPLC: t_(R)=10.07 min (Grad 1);ES-MS: m/e_(o)=394.9 and 396.9; NMR (DMSO-d6): 12.55/s (NH); 8.06/s(1H),7.25-7.5/several m's(6H), 7.07/“d”(1H); 7.03/s(1H); 6.98/“d”(1H);5.5-6.0/b (NH2); 5.12/s (2H).

Example 122

[0418]5-(3-Benzyloxy-phenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin4-ylamineIn a sealed tube 12.53 g (31.7 mmol)5-(3-benzyloxy-phenyl)-6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, 32ml (158.5 mmol) tin tetraethyl (Aldrich), and 7.32 g (6.34 mmol)tetrakis triphenylphosphin palladium are heated under Argon at 90° C.for 66 h (reaction control by HPLC and MS). After that time, thereaction suspension is filtered on hyflo and the solvent evaporated on arotavap under high vacuum at 50-60° C. The residue is partitionedbetween ethyl acetate and water. The organic phase is dried over sodiumsulfate and is evaporated. The residue is purified by chromatography onsilicagel (ethyl acetate-methanol 95:5). Crystallization is done fromacetone. Analytical HPLC: t_(R)=10.43 min (Grad 1); ES-MS:m/e_(o)=345.1; NMR (DMSO-d6): 11.65/s (NH); 8.03/s(1H), 7.25-7.5/m and6.85-7.1/m (9H), 5.5-6.0/b (NH2); 5.14/s (2H); 2.54/q (2H); 1.14/s (3H).

Example 123

[0419] cis andtrans-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester

[0420] A mixture of 1.26 g (2.74 mmol)5-(3-benzyloxy-phenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine,1.53 g (10.9 mmol) of powdered potassium carbonate and 2.92 g (10.9mmol) 18-crown-6 ether in 12 ml dry N,N-dimethylformamide is stirred for15 min at 80° C. 1.7 g (8.2 mmol) of3-Methanesulfonyloxy-cyclobutanecarboxylic acid methyl ester, dissolvedin 9 ml dry N,N-dimethylformamide, is added dropwise in 15 min. Afterstirring for 42 h at 80° C., work-up is effected by filtering thereaction mixture on hyflo and evaporating the solvent. The residue ispartitioned between water and ethyl acetate. The organic layer is driedover sodium sulfate and concentrated in vacuo. The crude product ispurified and separated by flash chromatography (hexane-ethyl acetate1:2). The ratio cis to trans isomer is about 70:30 (by HPLC, Grad25).

[0421] cis: Analytical HPLC: t_(R)=12.27 min (Grad 1); ES-MS:m/e_(o)=457.0; NMR (DMSO-d6): 8.12/s(1H), 7.3-7.5/several m's(6H),7.07/“d”(1H); 6.96/s(1H); 6.91/“d”(11H); 5.5-6.1/b (NH2); 5.15/s (2H);4.81/m (1H); 3.67/s (3H); 3.49/q (2H); 3.03/m (1H); 2.62/m (4H); 1.08/t(3H).

[0422] trans: Analytical HPLC: t_(R)=12.65 min (Grad 1); ES-MS:m/e_(o)=457.0; NMR (DMSO-d6): 8.37/s(1H); 7.3-7.5/several m's(6H),7.11/“d”(1H); 6.97/s(1H); 6.93/“d”(1H); 5.15/s (2H); 5.11/m (1H); 3.70/s(3H); 3.3-3.5/m (3H); 2.72/m (2H); 2.62/q (2H); 1.06/t (3H); NH2 notvisible.

Example 124

[0423]cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol

[0424] In analogy to Example 105, 0.73 g (1.56 mmol)cis-3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester of Example 123 are reduced with 69 mg (1.73 mmol)lithium aluminiumhydride in THF. Reaction time: 18 h at 0-5° C.Analytical HPLC: t_(R)=11.15 min (Grad 1); ES-MS: m/e_(o)=429.1; NMR(DMSO-d6): 8.10/s(1H); 7.3-7.5/several m's(6H), 7.04/“d”(1H);6.93/s(1H); 6.90/“d”(1H); 5.4-6.0/b (NH2); 5.15/s (2H); 4.75/m (1H);4.63/“t”(OH); 3.60/t (2H); 3.03 q (2H); 2.61/q (2H); 2.14/q (2H); 2.24/m(1H); 1.07/t (3H).

Example 125

[0425]trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol

[0426] In analogy to Example 105, 0.49 g (1.09 mmol)trans-3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methyl ester of Example 123 are reduced with 46 mg (1.18 mmol)lithium aluminiumhydride in THF. Reaction time: 17 h at 0-5° C.Analytical HPLC: t_(R)=10.91 min (Grad 1); ES-MS: m/e_(o)=429.1; NMR(DMSO-d6): 8.13/s(1H); 7.3-7.6/several m's(6H), 7.061/“d”(1H);6.95/s(1H); 6.90/“d”(1H); 5.4-6.0/b (NH2); 5.15/s (2H); 4.93/m (1H);4.681/“t” (OH); 3.60/m (2H); ca. 3.3-3.4/m (2H); 2.95/q (2H); 2.20/m(2H); 2.24/m (1H); 1.05/t (3H).

Example 126

[0427]cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0428] The title compound is prepared in a one pot reaction in analogyto Example 116 starting from 0.2 g (0.46 mmol)cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 124 and 0.18 g (0.92 mmol) p-toluenesulfonyl chloride in 2 mldry pyridine followed by 2 ml pyrrolidine. The reaction is controlled bytlc. Analytical HPLC: t_(R)=9.61 min (Grad 1); ES-MS: m/e_(o)=482.0; NMR(DMSO-d6; not all signals reported): 8.12/s(1H); 6.9-7.5/severalm's(6H), 7.05/“d”(1H); 6.95/s(1H); 6.92/“d”(1H); 5.4-6.0/b (NH2); 5.15/s(2H); 4.72/m (1H); 2.62/q (2H); 1.06/t (3H).

Example 127

[0429]cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0430] The title compound is prepared in analogy to Example 116 fromcis-{3-[4-amino-5(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 124, p-toluenesulfonyl chloride and N-methyl-piperazine.Analytical HPLC-MS: t_(R)=1.40 min (Grad 1); ES-MS: m/e_(o)=511.45.

Example 128

[0431]cis-7-(3-Azetidin-1-ylmethyl-cyclobutyl)₆-ethyl-5-{3-[(Z)-2-eth-(E)-ylidene-hexa-3,5-dienyloxy]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0432] The title compound is prepared in analogy to Example 116 fromcis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 124, p-toluenesulfonyl chloride and trimethylenimin (Fluka,Buchs, Switzerland). Analytical HPLC-MS: t_(R)=1.51 min; ES-MS:m/e_(o)=468.45.

Example 129

[0433]cis-1-{3-[4-Amino-S-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl-]-cyclobutylmethyl}-piperidin-4-ol

[0434] The title compound is prepared in analogy to Example 116 fromcis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanolof Example 124, p-toluenesulfonyl chloride and 4-hydroxypiperidine(Fluka, Buchs, Switzerland). Analytical HPLC-MS: t_(R)=1.49 min; ES-MS:m/e_(o)=512.48.

Example 130

[0435]cis-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-pyrrolidin-2-yl)-methanol

[0436] The title compound is prepared in analogy to Example 116 fromcis-{3-[4-amino-5-(3-benzoyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 124, p-toluenesulfonyl chloride and D-prolinol (Fluka, Buchs,Switzerland). Analytical HPLC-MS: t_(R)=1.48 min; ES-MS: m/e_(o)=512.48.

Example 131

[0437]cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-{3-[(tetrahydro-pyran-4-ylamino)-methyl]-cyclobutyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine

[0438] The title compound is prepared in analogy to Example 116 fromcis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanolof Example 124, p-toluenesulfonyl chloride and teztrahydropyran-4-ylamin(see Example 111). Analytical HPLC-MS: t_(R)=1.50 min; ES-MS:m/e_(o)=512.49.

Example 132

[0439] Test for activity against I induced IGF-IR autophosphorylationusing the cellular “Capture ELISA” test

[0440] The cellular “Capture ELISA” test is carried out as describedabove. The IC₅₀ values for some of the compounds of the presentinvention are given below: Compound from Example IC₅₀ (μM) 1 0.062 20.03 9 0.042 10 0.07 14 0.03 22 0.08 23 0.031 24 0.095 26 0.055 27 0.0528 0.05 31 0.03 49 0.04 50 0.011 51 0.03 57 0.018 70 0.05 75 0.05 770.05 81 0.08 83 0.052 88 0.057 90 0.09 95 0.08 96 0.05 98 0.04 102 0.06109 0.15 110 0.14 112 0.09 116 0.15 117 0.13

Example 23 Tablets

[0441] Tablets comprising 50 mg of active ingredient, for example one ofthe compounds of formula I described in Examples 1 to 131, and havingthe following composition are prepared in customary manner: Composition:active ingredient   50 mg wheat starch   150 mg lactose   125 mgcolloidal silicic acid  12.5 mg talc  22.5 mg magnesium stearate  2.5 mgTotal: 362.5 mg

[0442] Preparation: The active ingredient is mixed with a portion of thewheat starch, with the lactose and the colloidal silicic acid and themixture is forced through a sieve. A further portion of the wheat starchis made into a paste, on a water bath, with five times the amount ofwater and the powder mixture is kneaded with the paste until a slightlyplastic mass is obtained.

[0443] The plastic mass is pressed through a sieve of about 3 mm meshsize and dried, and the resulting dry granules are again forced througha sieve. Then the remainder of the wheat starch, the talc and themagnesium stearate are mixed in and the mixture is compressed to formtablets weighing 145 mg and having a breaking notch.

Example 134 Soft Capsules

[0444] 5000 soft gelatin capsules comprising each 50 mg of activeingredient, for example one of the compounds of formula I described inExamples 1 to 131, are prepared in customary manner. Composition: activeingredient 250 g Lauroglykol 2 liters

[0445] Preparation: The pulverized active ingredient is suspended inLauroglykol® (propylene glycol laurate, Gattefossé S.A., Saint Priest,France) and ground in a wet pulverizer to a particle size of approx. 1to 3 μm. 0.419 g portions of the mixture are then dispensed into softgelatin capsules using a capsule-filling machine.

1. A compound of formula I

wherein n is from 0 to 4, R₁ is hydrogen, unsubstituted or substitutedlower alkyl or halogen, R₂ is lower alkyl substituted by hydroxy,unsubstituted, mono- or disubstituted amino or by a heterocyclicradical; a radical R₅—(C═Y)-Z-, wherein R₅ is unsubstituted orsubstituted lower alkyl, unsubstituted, mono- or disubstituted amino, aheterocyclic radical, or free or etherifed hydroxy, Y is oxygen, sulfuror imino, and Z is either not present, lower alkyl or amino-lower alkyl;or a radical R₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstitutedor substituted lower alkyl, unsubstituted, mono- or disubstituted aminoor phenyl optionally substituted by lower alkyl, lower alkoxy or nitro,with the proviso that R₂ is not carboxy, lower alkoxycarbonyl or loweralkyl substituted by hydroxy if n is 0, R₁ is hydrogen, R₄ is benzyl andX is —O—, R₃ is lower alkyl, hydroxy-, amino- or halogen-substitutedlower alkyl, hydroxy, cyano, lower alkoxy, lower alkanoyl, loweralkanoyloxy, amino, mono- or di-lower alkylamino, lower alkanoylamino,carboxy, lower alkoxycarbonyl or halogen, wherein the R₃ substituentscan be selected independently of one another if n>1, R₄ is a radicalR₇—CR₈(R₉)-, wherein R₇ is cyclobutyl, cyclopentyl, cyclohexyl, phenyl,furyl, pyrrolyl, thienyl or pyridyl, said R₇ substitutents beingoptionally substituted by one or more radicals selected from lower alkyland halogen, and R₈ and R₉ are independently of each other hydrogen,lower alkyl or halogen, and X is selected from —O—, —NH— and —S—, or asalt thereof.
 2. A compound of formula I according to claim 1, wherein nis from 0 to 4, R₁ is hydrogen, unsubstituted or substituted lower alkylor halogen, R₂ is lower alkyl substituted by hydroxy, unsubstituted,mono- or disubstituted amino or by a heterocyclic radical; a radicalR₅—(C═Y)-Z-, wherein R₅ is unsubstituted or substituted lower alkyl,unsubstituted, mono- or disubstituted amino, a heterocyclic radical, orfree or etherified hydroxy, Y is oxygen, sulfur or imino, and Z iseither not present, lower alkyl or amino-lower alkyl; or a radicalR₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro, with theproviso that R₂ is not carboxy, lower alkoxycarbonyl or lower alkylsubstituted by hydroxy if n is 0, R₁ is hydrogen, R₄ is benzyl and X is—O—, R₃ is lower alkyl or lower alkoxy, wherein the R₃ substituents canbe selected independently of one another if n>1, R₄ is a radicalR₇—CR₈(R₉)-, wherein R₇ is cyclobutyl, cyclopentyl, cyclohexyl, phenyl,furyl, pyrrolyl, thienyl, pyridyl or phenyl substituted by one or moresubstitutents selected from lower alkyl and halogen, and R₈ and R₉ areindependently of each other hydrogen, lower alkyl or halogen, and X isselected from —O—, —NH— and —S—, or a salt thereof.
 3. A compound offormula I according to claim 1, wherein n is 0, R₁ Is hydrogen,unsubstituted or substituted lower alkyl or halogen, R₂ is lower alkylsubstituted by unsubstituted, mono- or disubstituted amino or by aheterocyclic radical; a radical R₅—(C═Y)-Z-, wherein R₅ is unsubstitutedor substituted lower alkyl, unsubstituted, mono- or disubstituted amino,a heterocyclic radical, or if Z is present is also free or etherifiedhydroxy, Y is oxygen, sulfur or imino, and Z is either not present,lower alkyl or amino-lower alkyl; or a radical R₆-sulfonylamino-loweralkyl, wherein R₆ is unsubstituted or substituted lower alkyl,unsubstituted, mono- or disubstituted amino or phenyl optionallysubstituted by lower alkyl, lower alkoxy or nitro, R₄ is benzyl, and Xis selected from —O—, —NH— and —S—, or a salt thereof.
 4. A compound offormula I according to claim 3, wherein n is 0, R₁ is hydrogen,unsubstituted or substituted lower alkyl or halogen, R₂ is lower alkylsubstituted by a substituted heterocyclic radical; a radicalR₅—(C═Y)-Z-, wherein R₅ is unsubstituted or substituted lower alkyl,unsubstituted, mono- or disubstituted amino, a heterocyclic radical, orif Z is present is also free or etherified hydroxy, Y is oxygen, sulfuror imino, and Z is either not present, lower alkyl or amino-lower alkyl,with the proviso that Z is not present or lower alkyl if R₅ is loweralkyl and Z is lower alkyl or amino-lower alkyl if R₅ is mono- ordisubstituted amino or a heterocyclic radical; or a radicalR₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted or substitutedlower alkyl, unsubstituted, mono- or disubstituted amino or phenyloptionally substituted by lower alkyl, lower alkoxy or nitro, R₄ isbenzyl, and X is selected from —O—, —NH— and —S., or a salt thereof. 5.A compound of formula I according to claim 3, wherein n is 0, R₁ ishydrogen, unsubstituted or substituted lower alkyl or halogen, R₂ islower alkyl substituted by amino, N-lower alkylamino, N,N-di-loweralkylamino or by an unsubstituted heterocyclic radical; or a radicalR₅—(C═Y)-Z-, wherein R₅ is lower alkyl, mono- or disubstituted amino ora heterocyclic radical, Y is oxygen, sulfur or imino, and Z isamino-lower alkyl if R₅ is lower alkyl and not present if R₅ is aheterocyclic radical or mono- or disubstituted amino, R₄ is benzyl, andX is selected from —O—, —NH— and —S—, or a salt thereof.
 6. A compoundof formula I according to claim 3, wherein n is 0, R₁ is hydrogen,unsubstituted or substituted lower alkyl or halogen, R₂ is lower alkylsubstituted by unsubstituted, mono- or disubstituted amino or by aheterocyclic radical having from 4 to 8 ring members and from 1 to 3heteroatoms whereby at least one heteroatom is nitrogen and the bindingof the heterocyclic radical to lower alkyl occurs via a nitrogen ringatom; a radical R₅—(C—Y)-Z-, wherein R₅ is lower alkyl, unsubstituted,mono- or disubstituted amino, a heterocyclic radical having from 4 to 8ring members and from 1 to 3 heteroatoms whereby at least one heteroatomis nitrogen and the binding of the heterocyclic radical occurs via anitrogen ring atom, lower alkyl substituted by said heterocyclic radicalor by one or more radicals selected independently of one another fromthe group consisting of amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, N,N-di-lower alkanoylamino, hydroxy,lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyl, loweralkanoyloxy, cyano, nitro, carboxy, lower alkoxycarbonyl, carbamoyl,amidino, guanidino, ureido, mercapto, lower alkylthio and halogen, or ifZ is present is also free or etherified hydroxy, Y is oxygen, sulfur orimino, and Z is either not present, lower alkyl or amino-lower alkyl; ora radical R₆-sulfonylamino-lower alkyl, wherein R₆ is unsubstituted orsubstituted lower alkyl, unsubstituted, mono- or disubstituted amino orphenyl optionally substituted by lower alkyl, lower alkoxy or nitro, R₄is benzyl, and X is selected from —O—, —NH— and —S—, or a salt thereof.7. A compound of formula I according to claim 3, wherein n is 0, R₁ ishydrogen, R₂ is amino-lower alkyl, N-lower alkylamino-lower alkyl,N,N-di-lower alkylamino-lower alkyl, morpholinyl-lower alkyl,piperidyl-lower alkyl, pyrrolidinyl-lower alkyl, loweralkyl-piperazinyl-lower alkyl, adamantanyl-amino-lower alkyl,hydroxy-piperidyl-lower alkyl, azepanyl-lower alkyl, di-loweralkyl-pyrrolidinyl-lower alkyl, azetidinyl-lower alkyl,aminocarbonyl-piperidyl-lower alkyl, pyridyl-piperazinyl-lower alkyl,thiomorpholinyl-lower alkyl, di-lower alkyl-morpholinyl-lower alkyl,aminocarbonyl-pyrrodinyl-lower alkyl, loweralkoxycarbonyl-piperazinyl-lower alkyl or phenyl-piperazinyl-loweralkyl; a radical R₅—(C═Y)-Z-, wherein R₅ is lower alkyl, amino, N-loweralkylamino, N,N-di-lower alkylamino, N-(phenyl-lower alkyl)amino,N-(lower alkyl-phenyl-lower alkyl)-amino, N-(lower alkoxy-phenyl-loweralkyl)-amino, N-(morpholinyl-lower alkyl)-amino, N,N-di-loweralkylamino-lower alkylamino, pyrrolidinyl, piperidyl, morpholinyl, loweralkyl-piperazinyl, piperidyl-lower alkyl, morpholinyl-lower alkyl, loweralkyl-piperazinyl-lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy,lower alkoxy-lower alkyl, lower alkoxy-lower alkoxy-lower alkyl,N,N-di-lower alkylamino-lower alkoxy, morpholinyl-lower alkoxy or loweralkyl-piperazinyl-lower alkoxy, Y is oxygen or imino, and Z is is eithernot present or amino-lower alkyl; or a radical R₆-sulfonylamino-loweralkyl, wherein R₆ is lower alkyl, lower alkyl-phenyl, loweralkoxy-phenyl, nitrophenyl or N,N-di-lower alkylamino, R₄ is benzyl, andX is —O—, or a salt thereof.
 8. A compound of formula I according toclaim 1, wherein n is 0, R₁ is hydrogen, lower alkyl or halogen, R₂ is aradical selected from the group consisting of hydroxy-lower alkyl,carboxy, lower alkoxycarbonyl, amino-lower alkyl, N-loweralkylamino-lower alkyl, (tetrahydropyranyl-amino)-lower alkyl,N,N-di-lower alkylamino-lower alkyl, N-lower alkylaminocarbonyl,N,N-di-lower alkylaminocarbonyl, guanidino-lower alkyl, loweralkyl-sulfonylamino-lower alkyl, lower alkoxy-phenyl-sulfonylamino-loweralkyl, lower alkyl-phenyl-sulfonylamino-lower alkyl,nitrophenyl-sulfonylamino-lower alkyl, N,N-di-loweralkylamino-sulfonylamino-lower alkyl, lower alkoxycarbonylamino-loweralkyl, lower alkoxy-lower alkoxycarbonylamino-lower alkyl, ureido-loweralkyl, N-lower alkylamino-carbonylamino-lower alkyl, N,N-di-loweralkylamino-carbonylamino-lower alkyl, N-(phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkyl-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkoxy-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(morpholinyl-loweralkyl)-amino-carbonylamino-lower alkyl, N,N-di-lower alkylamino-loweralkylamino-carbonylamino-lower alkyl, lower alkyl-carbonylamino-loweralkyl, piperidyl-lower alkyl-carbonylamino-lower alkyl,morpholinyl-lower alkyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-lower alkyl-carbonylamino-lower alkyl,morpholinyl-lower alkyl, piperidyl-lower alkyl, pyrrolidinyl-loweralkyl, [(hydroxy-lower alkyl)pyrrolidinyl]-lower alkyl, loweralkyl-piperazinyl-lower alkyl, adamantanyl-amino-lower alkyl,hydroxy-piperidyl-lower alkyl, azepanyl-lower alkyl, di-loweralkyl-pyrrolidinyl-lower alkyl, azetidinyl-lower alkyl,aminocarbonyl-piperidyl-lower alkyl, pyridyl-piperazinyl-lower alkyl,thiomorpholinyl-lower alkyl, di-lower alkyl-morpholinyl-lower alkyl,aminocarbonyl-pyrrodinyl-lower alkyl, loweralkoxycarbonyl-piperazinyl-lower alkyl, phenyl-piperazinyl-lower alkyl,lower alkoxy-lower alkylcarbonylamino-lower alkyl, lower alkoxy-loweralkoxy-lower alkylcarbonylamino-lower alkyl,pyrrolidinyl-carbonylamino-lower alkyl, piperidyl-carbonylamino-loweralkyl, morpholinyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-carbonylamino-lower alkyl, N,N-di-loweralkylamino-lower alkoxycarbonylamino-lower alkyl, morpholinyl-loweralkoxy-carbonylamino-lower alkyl and lower alkyl-piperazinyl-loweralkoxycarbonylamino-lower alkyl, with the proviso that R₂ is nothydroxy-lower alkyl, carboxy or lower alkoxycarbonyl if R₁ is hydrogen,R₄ is benzyl, and X is —O—, or a salt thereof.
 9. A compound of formulaI according to claim 3, wherein n is 0, R₁ is hydrogen, R₂ is a radicalselected from the group consisting of amino-lower alkyl, N-loweralkylamino-lower alkyl, N,N-di-lower alkylamino-lower alkyl, N-loweralkylaminocarbonyl, N,N-di-lower alkylaminocarbonyl, guanidino-loweralkyl, lower alkyl-sulfonylamino-lower alkyl, loweralkoxy-phenyl-sulfonylamino-lower alkyl, loweralkyl-phenyl-sulfonylamino-lower alkyl, nitrophenyl-sulfonylamino-loweralkyl, N,N-di-lower alkylamino-sulfonylamino-lower alkyl, loweralkoxycarbonylamino-lower alkyl, lower alkoxy-loweralkoxycarbonylamino-lower alkyl, ureido-lower alkyl, N-loweralkylamino-carbonylamino-lower alkyl, N,N-di-loweralkylamino-carbonylamino-lower alkyl, N-(phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkyl-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(lower alkoxy-phenyl-loweralkyl)-amino-carbonylamino-lower alkyl, N-(morpholinyl-loweralkyl)-amino-carbonylamino-lower alkyl, N,N-di-lower alkylamino-loweralkylamino-carbonylamino-lower alkyl, lower alkylcarbonylamino-loweralkyl, piperidyl-lower alkylcarbonylamino-lower alkyl, morpholinyl-loweralkylcarbonylamino-lower alkyl, lower alkyl-piperazinyl-loweralkylcarbonylamino-lower alkyl, morpholinyl-lower alkyl, piperidyl-loweralkyl, pyrrolidinyl-lower alkyl, lower alkyl-piperazinyl-lower alkyl,adamantanyl-amino-lower alkyl, hydroxy-piperidyl-lower alkyl,azepanyl-lower alkyl, di-lower alkyl-pyrrolidinyl-lower alkyl,azetidinyl-lower alkyl, aminocarbonyl-piperidyl-lower alkyl,pyridyl-piperazinyl-lower alkyl, thiomorpholinyl-lower alkyl, di-loweralkyl-morpholinyl-lower alkyl, aminocarbonyl-pyrrodinyl-lower alkyl,lower alkoxycarbonyl-piperazinyl-lower alkyl, phenyl-piperazinyl-loweralkyl, lower alkoxy-lower alkylcarbonylamino-lower alkyl, loweralkoxy-lower alkoxy-lower alkylcarbonylamino-lower alkyl,pyrrolidinyl-carbonylamino-lower alkyl, piperidyl-carbonylamino-loweralkyl, morpholinyl-carbonylamino-lower alkyl, loweralkyl-piperazinyl-carbonylamino-lower alkyl, N,N-di-loweralkylamino-lower alkoxycarbonylamino-lower alkyl, morpholinyl-loweralkoxycarbonylamino-lower alkyl and lower alkyl-piperazinyl-loweralkoxycarbonylamino-lower alkyl, R₄ is benzyl, and X is —O—, or a saltthereof.
 10. A compound of formula I according to claim 3, selected fromthe group consisting ofcis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-3-[amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid dimethylamide;trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutanecarboxylicacid dimethylamide;cis-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutanecarboxylicacid methylamide;trans-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-y]-cyclobutanecarboxylicacid methylamide;cis-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)₇H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-(3-dimethylaminomethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrmidin-4-ylamine;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutylmethyl}}-guanidine;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cylobutylmethyl}-guanidine;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cylcobutylmethyl}-methanesulfonamide;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutylmethyl}-methanesulfonamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-4-methoxy-benzenesulfonamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-4-methyl-benzenesulfonamide;trans-N-[3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl]-4-nitro-benzenesulfonamide;propane-2-sulfonic acidtrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;ethanesulfonic acidtrans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;N-dimethyl-sulfamidetrans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;N-dimethyl-sulfamidecis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-amide;trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid methyl ester;cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid methyl ester;trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-y]-cyclobutylmethyl}-carbamicacid 2-methoxy-ethyl ester;cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2.3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-methoxy-ethyl ester;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-urea;cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}3-propyl-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-propyl-urea;trans-1-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-3-isopropyl-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-isopropyl-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-y]-cyclobutylmethyl}-3-butyl-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yg-cyclobutylmethyl}-3-butyl-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-tert-butyl-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl]3-tert-butyl-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-y]-cyclobutylmethyl}-3-benzyl-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-y]-cyclobutylmethyl}-3-(3-methyl-benzyl)-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-methyl-benzyl)-urea;cis-1-(3-[4-amino-5-(3-benyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(4-methoxy-benzyl)-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-3(2-morpholin-4-yl-ethyl)-urrea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(2-morpholin4-yl-ethyl)-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-3-(2-dimethylamino-ethyl)-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yq-cyclobutylmethyl}-3-(2-dimethylamino-ethyl)-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-3(3-morpholin-4-yl-propyl)-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-morpholin4-yl-propyl)-urea;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3(3-dimethylamino-propyl)-urea;cis-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-(3-dimethylamino-propyl)-urea;trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-urea;cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl]-urea;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamide;cis-N-(3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isobutyramide;cis-N-{3-[amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isobutyramide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2,2-dimethyl-propionamide;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2,2-dimethyl-propionamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-piperidin-1-yl-acetamide;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-piperidin-1-yl-acetamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-2-morpholin-4-yl-acetamide;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-morpholin-4-yl-acetamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-(4-methyl-piperazin-1-yl)-acetamide;cis-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl)-2-(4-methyl-piperazin-1-yl)-acetamide;trans-5-(3-benzyloxy-phenyl)-7-(3-morpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-(3-piperidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;trans-7-[3-(adamantan-1-ylaminomethyl)-cyclobutyl]-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-y-]-cyclobutylmethyl}-piperidin-4-ol;trans-7-(3-azepan-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-benzyloxy-phenyl)₇-[3-(2,5-dimethyl-pyrrolidin-1-ylmethyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-7-(3-azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)₇H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-1-3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidine-3-carboxylicacid amide;trans-5-(3-benzyloxy-phenyl)₇-[3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;trans-5-(3-benyloxy-phenyl)-7-(3-thiomorpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-benzyloxy-phenyl)-7-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-(S)-1-{3-[4-amino-5(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-pyrrolidine-2-carboxylicacid amide;cis-7-(3-azepan-1-ylmethyl-cyclobutyl)-5(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-1{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidin4-ol;cis-4-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperazine-1-carboxylicacid ethyl ester;cis-5-(3-benzyloxy-phenyl)-7-[3-(4-phenyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-5-(3-benzyloxy-phenyl)-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-5-(3-benzyloxy-phenyl)-7-(3-thiomorpholin-4-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-5-(3-benzyloxy-phenyl)-7-[3-(2,6-dimethyl-morpholin-4-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;cis-(R)-1-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutylmethyl}-pyrrolidine-2-carboxylicacid amide;cis-1-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidine-3-carboxylicacid amide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-2-ethoxy-acetamide;trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutylmethyl}-2-(2-methoxy-ethoxy)-acetamide;trans-1-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-methyl-urea;cis-1-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-methyl-urea;trans-pyrrolidine-1-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}amide;trans-piperidine-1-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;trans-morpholine-4-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;trans-3-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-1,1-dimethyl-urea;trans-4-methyl-piperazine-1-carboxylic acid{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-amide;trans-3-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-1,1-diethyl-urea;trans-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-diethylamino-ethyl ester;trans-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-morpholin-4-yl-ethyl ester;trans-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pydmidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-(4-methyl-piperazin-1-yl)-ethyl ester;trans-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrmidin-7-yl]-cyclobutylmethyl}-carbamicacid 2-dimethylamino-ethyl ester,trans-{3-[4-amino-5-(3-benyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-carbamicacid ethyl ester;trans-4-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperazine-1-carboxylicacid ethyl ester;cis-5-(3-benzyloxy-phenyl)-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-7-(3-azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;and pharmaceutically acceptable salts thereof.
 11. A compound of formulaI according to claim 1, selected from the group consisting oftrans-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pydmidin-7-yl]-cylcobutanecarboxylicacid methylester;trans-3-[4-Amino-5-(3-benzyloxy-phenyl)₆-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester;trans-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol;cis-3-[4-Amino-5-(3-benyloxy-phenyl)-6-bromo-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester;cis-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester;cis-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol;cis-3-[4-Amino-5-(3-benyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester;trans-3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutanecarboxylicacid methyl ester;cis-{3-[4-Amino-5(3-benyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol;trans-{3-[4-Amino-5-(3-benyloxy-phenyl)₆-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol;and pharmaceutically acceptable salts thereof.
 12. A compound of formulaI according to claim 3, selected from the group consisting oftrans-5-(3-Benzyloxy-phenyl)-6-methyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;trans-5-(3-Benzyloxy-phenyl)-6-methyl-7-[3-(4-methyl-piperazin-1-ylmethyl)cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidin-4-ol;trans-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-5-(3-Benzyloxy-phenyl)-6-methyl-7-{3-[(tetrahydro-pyran-4-ylamino)-methyl]-cylcobutyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;trans-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-pyrrolidin-2-yl)-methanol;cis-5-(3-Benzyloxy-phenyl)-6-methyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;cis-5-(3-Benzyloxy-phenyl)-6-methyl-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin4-ylamine;cis-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-piperidin-4-ol;cis-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-pyrrolidin-2-yl)-methanol;cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-(3-pyrrolidin-1-ylmethyl-cyclobutyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-[3-(4-methyl-piperazin-1-ylmethyl)-cyclobutyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-7-(3-Azetidin-1-ylmethyl-cyclobutyl)-6-ethyl-5-{3-[(Z)-2-eth-(E)-ylidene-hexa-3,5-dienyloxy]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cylcobutylmethyl}-piperidin-4-ol;cis-((R)-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pydmidin-7-yl]-cylcobutylmethyl}-pyrrolidin-2-yl)-methanol;cis-5-(3-Benzyloxy-phenyl)-6-ethyl-7-{3-[(tetrahydro-pyran-4-ylamino)-methyl]-cyclobutyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine;and pharmaceutically acceptable salts thereof.
 13. A compound of formulaI, or a pharmaceutically acceptable salt thereof, according to any oneof claims 1 to 12 for use in a method for the treatment of the human oranimal body.
 14. A pharmaceutical composition comprising a compound offormula I or a pharmaceutically acceptable salt thereof according to anyone of claims 1 to 12, together with at least one pharmaceuticallyacceptable carrier.
 15. Use of a compound of formula I according to anyone of claims 1 to 12, or a pharmaceutically acceptable salt thereof,for the preparation of a pharmaceutical composition for the treatment ofa disease which responds to an inhibition of the IGF-IR-dependent cellproliferation.
 16. Use of a compound of formula I according to any oneof claims 1 to 12, or a pharmaceutically acceptable salt thereof, forthe preparation of a pharmaceutical composition for the treatment of adisease which responds to an Inhibition of the IGF-IR tyrosine kinase.17. A process for the preparation of a compound of formula I accordingto claim 1 or of a salt of such a compound, characterized in that a) inorder to prepare a compound of formula I, in which R₂ is lower alkylsubstituted by amino, a compound of formula II

 wherein n, R₁, R₃, R₄ and X have the meanings as defined for a compoundof formula I according to claim 1, is reacted with hydrazine; b) inorder to prepare a compound of formula I, in which R₂ is a radicalR₅—(C═Y)-Z- wherein R₅ is unsubstituted, mono- or disubstituted amino, Yis oxygen and Z is not present or lower alkyl, a compound of formula III

 in which R₁₀ is a radical HO-(C═O)-Z- wherein Z is not present or loweralkyl, and n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₅—H wherein R₅ is unsubstituted, mono- or disubstitutedamino; c) in order to prepare a compound of formula I, in which R₂ islower alkyl substituted by mono- or disubstituted amino, a compound offormula I, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅ is mono- ordisubstituted amino, Y is oxygen and Z Is not present or lower alkyl, isreacted with lithium aluminium hydride; d) in order to prepare acompound of formula I, in which R₂ is lower alkyl substituted by mono-or disubstituted amino or by a heterocyclic radical containing at leastone nitrogen ring atom whereby the binding of the heterocyclic radicalto lower alkyl occurs via a nitrogen ring atom, a compound of formula IV

 in which R₁₁, is lower alkyl substituted by 4-methylphenylsulfonyloxyand n, R₁, R₃, R₄ and X have the meanings as defined for a compound offormula I according to claim 1, is reacted with a compound of theformula R₁₇—H in which R₁₇ is mono- or disubstituted amino or aheterocyclic radical containing at least one nitrogen ring atom whereinthe heterocyclic radical is attached to the hydrogen atom of R₁₇—H via anitrogen ring atom; e) in order to prepare a compound of formula I, inwhich R₂ is a radical R₆-sulfonylamino-lower alkyl wherein R₆ has themeanings as defined for a compound of formula I according to claim 1, acompound of formula I according to claim 1, in which R₂ is amino-loweralkyl, is reacted with R₆-sulfonyl halide; f) in order to prepare acompound of formula I, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅is free or etherifled hydroxy, Y is oxygen and Z is amino-lower alkyl, acompound of formula I according to claim 1, in which R₂ is amino-loweralkyl, is reacted with a compound of the formula R₅—(C═O)-Halogenwherein R₅ is free or etherifed hydroxy; g) in order to prepare acompound of formula I, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅is unsubstituted or monosubstituted amino, Y is oxygen or sulfur and Zis amino-lower alkyl, a compound of formula I according to claim 1, inwhich R₂ is amino-lower alkyl, is reacted with a compound of the formulaR₁₂—N═C═Y wherein Y is oxygen or sulfur, the radical R₁₂-NH—corresponding to unsubstituted or monosubstituted amino R₅; h) in orderto prepare a compound of formula I, in which R₂ is a radical R₅—(C═Y)-Z-wherein R₅ is unsubstituted, mono- or disubstituted amino or aheterocyclic radical containing at least one nitrogen ring atom wherebythe binding of the heterocyclic radical occurs via a nitrogen ring atom,Y is oxygen and Z is amino-lower alkyl, a compound of formula Iaccording to claim 1, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅ isimidazol-1-yl, Y is oxygen and Z is amino-lower alkyl, is reacted with acompound of the formula R₅—H, in which R₅ is unsubstituted, mono- ordisubstituted amino, or a heterocyclic radical which contains at leastone nitrogen ring atom; i) in order to prepare a compound of formula I,in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅ is unsubstituted orsubstituted lower alkyl, Y is oxygen and Z is amino-lower alkyl, acompound of formula I according to claim 1, in which R₂ is amino-loweralkyl, is reacted with a compound of the formula R₅—(C═O)-Halogenwherein R₅ is unsubstituted or substituted lower alkyl; j) In order toprepare a compound of formula I, in which R₂ is a radical R₅—(C═Y)-Z-wherein R₅ is lower alkyl substituted by a heterocyclic radicalcontaining at least one nitrogen ring atom whereby the binding of theheterocyclic radical to lower alkyl occurs via a nitrogen ring atom, Yis oxygen and Z is amino-lower alkyl, a compound of formula V

 in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₁₈—H in which R₁₈ is a heterocyclic radical containingat least one nitrogen ring atom wherein the heterocyclic radical isattached to the hydrogen atom of R₁₈—H via a nitrogen ring atom; k) inorder to prepare a compound of formula I, in which R₂ is a radicalR₅—(C═Y)-Z- wherein R₅ is lower alkylamino wherein the lower alkylmoiety is substituted by unsubstituted, mono or disubstituted amino orby a heterocyclic radical containing at least one nitrogen ring atomwhereby the binding of the heterocyclic radical to the lower alkylmoiety occurs via a nitrogen ring atom, Y is oxygen or sulfur and Z isamino-lower alkyl, a compound of formula VI

 in which Y is oxygen or sulfur and n, R₁, R₃, R₄ and X have themeanings as defined for a compound of formula I according to claim 1, isreacted with a compound of the formula R₁₃—H, in which R₁₃ isunsubstituted, mono- or disubstituted amino or a heterocyclic radicalcontaining at least one nitrogen ring atom wherein the heterocyclicradical is attached to the hydrogen atom of R₁₃—H via a nitrogen ringatom; l) in order to prepare a compound of formula I, in which R₂ is aradical R₅—(C═Y)-Z- wherein R₅ Is lower alkoxy substituted byunsubstituted, mono- or disubstituted amino or by a heterocyclic radicalcontaining at least one nitrogen ring atom whereby the binding of theheterocyclic radical to the lower alkyl moiety of lower alkoxy occursvia a nitrogen ring atom, Y is oxygen and Z is amino-lower alkyl, acompound of formula VII

 in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof the formula R₁₄—H, in which R₁₄ is unsubstituted, mono- ordisubstituted amino or a heterocyclic radical containing at least onenitrogen ring atom wherein the heterocyclic radical is attached to thehydrogen atom of R₁₄—H via a nitrogen ring atom; m) in order to preparea compound of formula I, in which R₁ is halogen, a compound of formula Iaccording to claim 1, in which R₁ is hydrogen, is reacted withN-halosuccinimide; n) in order to prepare a compound of formula I, inwhich R₁ is lower alkyl, a compound of formula I according to claim 1,in which R₁ is halogen, is reacted with tetra(lower alkyl) tin; o) inorder to prepare a compound of formula I, a compound of formula IX

 in which n, R₁, R₃, R₄ and X have the meanings as defined for acompound of formula I according to claim 1, is reacted with a compoundof formula X

 in which R₂ has the meanings as defined for a compound of formula Iaccording to claim 1; p) in order to prepare a compound of formula I, inwhich R₂ is lower alkyl substituted by hydroxy wherein hydroxy isattached to a primary carbon atom, a compound of formula I according toclaim 1, in which R₂ is a radical R₅—(C═Y)-Z- wherein R₅ is etherifledhydroxy, Y is oxygen and Z is not present or C₁-C₆alkyl, is reacted withlithium aluminiumhydride; or q) in order to prepare a compound offormula I, in which R₂ is lower alkyl substituted by hydroxy whereinhydroxy is attached to a secondary or tertiary carbon atom, a compoundof formula XI

in which R₁₅ is a radical R₁₆—(C═O)-Q- wherein R₁₆ is hydrogen orC₁-C₅alkyl and Q is not present or C₁-C₅alkyl, is reacted with aGrignard reagent of the formula C₁-C₆alkyl-Mg-halide; whereby functionalgroups which are present in the starting compounds of processes a) to q)and are not intended to take part in the reaction, are present inprotected form if necessary, and protecting groups that are present arecleaved, whereby said starting compounds may also exist in the form ofsalts provided that a salt-forming group is present and a reaction insalt form is possible, and, if so desired, a compound of formula I thusobtained is converted into another compound of formula I, a freecompound of formula I is converted into a salt, an obtained salt of acompound of formula I is converted into the free compound or anothersalt, and/or a mixture of isomeric compounds of formula I is separatedinto the individual isomers.